Asymmetric ureas and medical uses thereof

ABSTRACT

Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the ghrelin receptor. The compounds have the general formula (I):

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §365(a) to PCTApplication No. PCT/CN2011/000298, filed Feb. 25, 2011, and under 35U.S.C. §119(e) to Provisional U.S. Application No. 61/466,070, filedMar. 22, 2011. The disclosure of PCT Application No. PCT/CN2011/000298and U.S. Application No. 61/466,070 are hereby incorporated by referencein their entirety.

FIELD OF THE INVENTION

The present invention relates to novel compounds based on asymmetricureas, and medical uses thereof, particularly in the treatment ofmedical conditions modulated by the ghrelin receptor.

BACKGROUND

The growth hormone secretagogue receptor (GHS-R) regulates a number ofphysiological processes, including growth hormone (GH) release,metabolism, and appetite. Ghrelin, a circulating hormone producedpredominantly by endocrine cells in the stomach, is its endogenousligand. Ghrelin is a 28 amino acid peptide with an acyl side chainrequired for biological activity (Kojima et al., Nature, 402, 656-660,1999). Ghrelin has been shown to stimulate growth hormone (GH) releaseand to increase food intake when administered both centrally andperipherally (Wren et al., Endocrinology, 141, 4325-4328, 2000).

Endogenous levels of ghrelin rise on fasting and fall on re-feeding inhumans (Cummings et al., Diabetes, 50, 1714-1719, 2001). Ghrelin alsoappears to play a role in maintaining long term energy balance andappetite regulation. Chronic administration of ghrelin in rodents leadsto hyperphagia and weight gain that are independent of growth hormonesecretion (Tschop et al., Nature, 407, 908-913, 2000). Circulatingghrelin levels decrease in response to chronic overfeeding and increasein response to chronic negative energy balance associated with anorexiaor exercise. Obese people generally have low plasma ghrelin levels(Tschop et al., Diabetes, 50, 707-709, 2001) accordingly to thephysiological response of the body in reducing calories intake.Intravenous ghrelin is effective in stimulating food intake in humans. Arecent study showed a 28% food intake increase from a buffet meal with aghrelin infusion compared with saline control (Wren et al., J ClinEndocrinology and Metabolism, 86, 5992, 2001).

In view of the above experimental evidence, compounds that modulateghrelin receptor activity have been proposed for preventing and/ortreating disorders associated with ghrelin receptor physiology. Forexample, antagonists at ghrelin receptor may reduce appetite, reducefood intake, induce weight loss and treat obesity without affecting orreducing the circulating growth hormone levels. On the other hand,agonists at ghrelin receptor may be useful in stimulating food intakeand thus be useful in treating eating disorders, for example anorexianervosa, or in treating cachexia resulting from cancer, AIDS or ChronicObstructive Pulmonary Disease (COPD). Ghrelin agonists may also beuseful as gastroprokinetic agents which can enhance gastrointestinalmotility by increasing the frequency of contractions in the smallintestine or making them stronger, but without disrupting their rhythm.Gastroprokinetic agents are used to relieve gastrointestinal symptomssuch as abdominal discomfort, bloating, constipation, heart burn,nausea, and vomiting, and are used to treat a number of gastrointestinaldisorders, including but not limiting to, irritable bowel syndrome,gastritis, acid reflux disease, gastroparesis, and functional dyspepsia.Furthermore, compounds that modulate ghrelin receptor activity can alsobe used to prevent or treat diseases related to substance abuse, forexample, alcohol or drug (e.g., amphetamines, barbiturates,benzodiazepines, cocaine, methaqualone, and opioids) abuse, which refersto a maladaptive pattern of use of a substance that is not considereddependent.

A number of compounds acting on the ghrelin receptor have been reportedin the literature. YIL-781, for example, is a small molecule ghrelinreceptor antagonist from Bayer that reportedly improves glucosetolerance, suppress appetite and promote weigh loss (Esler et al.,Endocrinology 148 (11):5175-5185); LY444711 is an orally active ghrelinreceptor agonist from Lilly that reportedly induces adiposity bystimulating food consumption and sparing fat utilization (Bioorg. & Med.Chem. Lett., 2004, 14, 5873-5876); Anamorelin is an orally availableghrelin receptor small molecule agonist from Helsinn Therapeutics thatis in clinical trials for the treatment of anorexia and cachexia incancer patients. Other small molecule ghrelin receptor modulators can befound in WO 2008/092681, US 2009/0253673, WO 2008/148853, WO2008/148856, US 2007/0270473 and US 2009/0186870.

In view of the above, it is desirable to find new compounds whichmodulate ghrelin receptor activity with enhanced efficacy and fewerundesirable side effects.

SUMMARY

In view of the foregoing, the inventors have developed a novel class ofcompounds particularly well-suited for modulating the ghrelin receptorand having the general formula (I):

with R and R₁-R₁₄ as defined herein, and pharmaceutically acceptablesalts or adducts thereof

Compounds of formula (I), also known as asymmetric ureas, areparticularly useful for preventing and/or treating diseases that arepathophysiologically related to the ghrelin receptor in a subject.Accordingly, in another embodiment the invention provides a method oftreating a disease that is mediated by the ghrelin receptor, comprisingadministering to said subject a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt or adductthereof.

Also disclosed are pharmaceutical compositions for preventing and/ortreating diseases which are pathophysiologically related to ghrelinreceptor in a subject, comprising a therapeutically effective amount ofa compound of formula (I), or a pharmaceutically acceptable salt oradduct thereof, and one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION

Before the present compounds, compositions, articles, devices, and/ormethods are disclosed and described, it is to be understood that theyare not limited to specific synthetic methods or specific treatmentmethods unless otherwise specified, or to particular reagents unlessotherwise specified, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to belimiting.

Materials

A. Compounds

Disclosed are compounds, and pharmaceutically acceptable salts oradducts thereof, represented by formula (I):

wherein:

R is selected from the group consisting of aryl, arylalkyl, carbocyclicring, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl andheteroarylalkyl, optionally substituted with one or more independentR¹⁰³ substituents;

R₁ is selected from the group consisting of hydrogen, hydroxy,hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy,alkoxyalkyl, —C(O)R¹⁰¹, —C(O)OR¹⁰¹, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, each optionallyindependently substituted with one or more independent R¹⁰³substituents;

R₂ is hydrogen or R₁ and R₂, together with the atoms connecting thesame, form a fused or non-fused mono, bicyclic or tricyclic heterocyclicor carbocyclic ring which is optionally independently substituted withone or more R¹⁰³ substituents;

R₃ is selected from the group consisting of hydrogen, alkyl, alkenyl,cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl, heteroarylalkyl, —C(O)R¹⁰¹, —C(O)OR¹⁰¹, —C(O)NR¹⁰¹R¹⁰²,—S(O)₂R¹⁰², —SR¹⁰¹ and —S(O)₂NR¹⁰¹NR¹⁰², optionally substituted with oneor more independent R¹⁰³ substituents;

R₄ is selected from the group consisting of alkyl, alkenyl, cycloalkyl,aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,heteroarylalkyl, —OR¹⁰³, NR¹⁰¹R¹⁰², —C(O)R¹⁰¹, —C(O)OR¹⁰¹,—C(O)NR¹⁰¹R¹⁰², -alkylNR¹⁰¹R¹⁰², —S(O)₂R¹⁰², —SR¹⁰¹ and —S(O)₂NR¹⁰¹R¹⁰²,optionally substituted with one or more independent R¹⁰³ substituents;or R₃ and R₄, together with the atoms connecting R₃ and R₄, form a fusedor non-fused mono, bicyclic or tricyclic heterocyclic or carbocyclicring which is optionally independently substituted with one or more R¹⁰³substituents;

R₅ is selected from the group consisting of alkyl, alkenyl, cycloalkyl,aryl, arylalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, oxide(═O), —C(O)R¹⁰¹, —C(O)OR¹⁰¹, —C(O)NR¹⁰¹R¹⁰², —S(O)₂R¹⁰², —SR¹⁰¹ and—S(O)₂NR¹⁰¹R¹⁰²;

R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are each independentlyselected from the group consisting of hydrogen, cyano, —NO₂, —OR¹⁰¹,hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy,alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl, heteroarylalkyl, —C(O)R¹⁰¹, —C(O)OR¹⁰¹, —C(O)NR¹⁰¹R¹⁰²,NR¹⁰¹R¹⁰², —NR¹⁰¹S(O)₂R¹⁰², —NR¹⁰¹C(O)R¹⁰², —S(O)₂R¹⁰², —SR¹⁰¹ and—S(O)₂NR¹⁰¹R¹⁰², each optionally independently substituted with one ormore independent R¹⁰³ substituents; or any two or more substituentsselected from the group consisting of R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃and R₁₄ together with the atoms connecting the same, form a fused ornon-fused mono, bicyclic or tricyclic heterocyclic or carbocyclic ringwhich is optionally independently substituted with one or more R¹⁰³substituents; and

R¹⁰¹, R¹⁰² and R¹⁰³ are each independently selected from the groupconsisting of hydrogen, cyano, —NO₂, hydroxy, amino, alkyl, alkenyl,cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl,—C(O)R¹⁰⁴, —C(O)OR¹⁰⁴, —C(O)NR¹⁰⁴R¹⁰⁵, —NR¹⁰⁴R¹⁰⁵, —NR¹⁰⁴S(O)₂R¹⁰⁵,—NR¹⁰⁴C(O)R¹⁰⁵, —S(O)₂R¹⁰⁴, —SR¹⁰⁴ and —S(O)₂NR¹⁰⁴R¹⁰⁵, each optionallyindependently substituted with one or more independent R¹⁰³substituents; or R¹⁰¹, R¹⁰², together with the atoms connecting thesame, form a fused or non-fused mono, bicyclic or tricyclic heterocyclicor carbocyclic ring which is optionally independently substituted withone or more R¹⁰³ substituents; and

R¹⁰⁴ and R¹⁰⁵ are each independently selected from the group consistingof hydrogen, cyano, —NO₂, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl,cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl.

In some forms, the compounds as presently disclosed are compounds offormula (I), or pharmaceutically acceptable salts or adducts thereof,wherein R is aryl or heteroaryl. In some other forms, the compounds aspresently disclosed are compounds of formula (I), or pharmaceuticallyacceptable salts or adducts thereof, wherein R is R is selected from thegroup consisting of phenyl, naphthalene, tetrahydronaphthalenyl,indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl,benzonaphthenyl, fluorenyl, indolizinyl, pyrindinyl, pyranopyrrolyl,4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl,indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl,phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl,benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl,benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl,benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl,benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, andtetrahydroisoquinolinyl, which is optionally independently substitutedwith from one to six substituents independently selected from the groupconsisting of hydrogen, halogen, alkoxy, haloalkyl, cyano, —NO₂, —OR¹⁰¹,hydroxy, amino, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl,—C(O)R¹⁰¹, —C(O)OR¹⁰¹, —C(O)NR¹⁰¹R¹⁰², —NR¹⁰¹R¹⁰², —NR¹⁰¹S(O)₂R¹⁰²,—NR¹⁰¹C(O)R¹⁰², —S(O)₂R¹⁰², —SR¹⁰¹ and —S(O)₂NR¹⁰¹R¹⁰².

In some forms, the compounds as presently disclosed are compounds offormula (I), or pharmaceutically acceptable salts or adducts thereof,wherein R is phenyl or naphthalene which is optionally independentlysubstituted with from one to six substituents independently selectedfrom the group consisting of hydrogen, chloro, fluoro, bromo,trifluoromethyl, cyano, methoxy, ethoxy, methyl and ethyl.

In some forms, the compounds as presently disclosed are compounds offormula (I), or pharmaceutically acceptable salts or adducts thereof,wherein R₁ is selected from the group consisting of hydrogen, alkoxy,alkoxyalkyl, —OR¹⁰¹, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl,cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl and heteroarylalkyl. In some other forms, the compounds aspresently disclosed are compounds of formula (I), or pharmaceuticallyacceptable salts or adducts thereof, wherein R₁ is selected from thegroup consisting of alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl,arylalkyl and heteroarylalkyl. In some other forms, the compounds aspresently disclosed are compounds of formula (I), or pharmaceuticallyacceptable salts or adducts thereof, wherein R₁ is selected from thegroup consisting of methyl, —CH₂OH, and —CH₂—O—CH₂-phenyl.

In some other forms, the compounds as presently disclosed are compoundsof formula (I), or pharmaceutically acceptable salts or adducts thereof,wherein R₃ is hydrogen, alkyl or cycloalkyl.

In some forms, the compounds as presently disclosed are compounds offormula (I), or pharmaceutically acceptable salts or adducts thereof,wherein R₄ is selected from the group consisting of alkyl, cycloalkyl,hydroxy, amino, alkoxy, alkylamino, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and aminoalkyl. Insome other forms, the compounds as presently disclosed are compounds offormula (I), or pharmaceutically acceptable salts or adducts thereof,wherein R₄ is methyl, ethyl, benzyl, or benzyl substituted with from oneto five substituents independently selected from the group consisting ofmethyl, fluoro, chloro, trifluoromethyl, methoxy, cyano and hydroxy.

In some forms, the compounds as presently disclosed are compounds offormula (I), or pharmaceutically acceptable salts or adducts thereof,wherein R₅ is selected from the group consisting of alkyl, cycloalkyl,oxide (═O), aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl, heteroarylalkyl, —C(O)R¹⁰¹, —C(O)OR¹⁰¹ and —C(O)NR¹⁰¹R¹⁰².In some other forms, the compounds as presently disclosed are compoundsof formula (I), or pharmaceutically acceptable salts or adducts thereof,wherein R₅ is methyl.

In some forms, the compounds as presently disclosed are compounds offormula (I), or pharmaceutically acceptable salts or adducts thereof,wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are eachindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, —C(O)OR¹⁰¹, and -alkylOR¹⁰³. In some other forms, thecompounds as presently disclosed are compounds of formula (I), orpharmaceutically acceptable salts or adducts thereof, wherein R₈ and R₉are each independently hydrogen, alkyl, cycloalkyl, —C(O)OR¹⁰¹, or-alkylOR¹⁰³. In some other forms, the compounds as presently disclosedare compounds of formula (I), or pharmaceutically acceptable salts oradducts thereof, wherein R₈ and R₉ are each independently hydrogen,methyl, ethyl, —C(═O)OEt, or —CH₂OH. In some other forms, the compoundsas presently disclosed are compounds of formula (I), or pharmaceuticallyacceptable salts or adducts thereof, wherein R₈ and R₉, together withthe atom connecting them, form a cycloalkyl ring. In some forms, thecompounds as presently disclosed are compounds of formula (I), orpharmaceutically acceptable salts or adducts thereof, wherein saidcycloalkyl ring as formed by R₈ and R₉ together with the atom connectingthem, is cyclopropane.

In some forms, the compounds as presently disclosed are compounds offormula (I), or pharmaceutically acceptable salts or adducts thereof,wherein the compound of formula (I) is a compound selected from thegroup consisting of:

Compound No. Chemical Structure Chemical Name GA1

1-methyl-3-((R)-1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA2

1-methyl-3-((S)-1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA3

1-methyl-3-(1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA4

3-(1-(4-methoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA5

1-benzyl-3-((R)-1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA6

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-methoxybenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA7

3-(1-(2,3-dichlorophenyl)ethyl)-1- (2-fluorobenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA8

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA9

3-(1-(2,3-dichlorophenyl)ethyl)-1- methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA10

3-((R)-1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-(1,3-dimethylpiperidin-4-yl)-1-(3- methoxybenzyl)urea, GA11

1-benzyl-3-(1-(2,3- dichlorophenyl)propyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA12

3-((S)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA13

3-((R)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA14

3-(1-(2,3-dichlorophenyl)ethyl)-1- methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA15

1-benzyl-3-((S)-1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA16

1-benzyl-3-((R)-1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA17

1-benzyl-3-(1-(naphthalcn-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA18

3-(1-(2,3-dichlorophenyl)propyl)- 1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA19

3-(1-(2,3-difluorophenyl)ethyl)-1- methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA20

1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA21

1-benzyl-3-(1-(2,3- difluorophenyl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA22

1-benzyl-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA23

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(l,3,3-trimethylpiperidin-4-yl)urea, GA24

3-(1-(2,3-dichlorophenyl)ethyl)-1- methyl-1-(1,2,2,5,5-pentamethylpiperidin-4-yl)urea, GA25

methyl 2-(3-methyl-3-(1,3,3- trimethylpiperidin-4-yl)ureido)-2-(naphthalen-1-yl)acetate, GA26

3-(2-hydroxy-1-(naphthalen-1- yl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA27

1-(4-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA28

1-benzyl-1-(3,3-diethyl-1- methylpiperidin-4-yl)-3-((S)-1-(naphthalen-1-yl)ethyl)urea, GA29

1-benzyl-1-(3,3-diethyl-1- methylpiperidin-4-yl)-3-((R)-1-(naphthalen-1-yl)ethyl)urea, GA30

1-benzyl-1-(3,3-diethyl-1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA31

3-(2-(benzyloxy)-1-(naphthalen-1- yl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA32

ethyl 4-(1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)ureido)-1,3-dimethylpiperidine-3-carboxylate, GA33

3-((R)-1-(2,3- dichlorophenyl)ethyl)-1-(3- methoxybenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA34

3-(2-cyclopropyl-1-(2,3- dichlorophenyl)ethyl)-1-(3-methoxybenzyl)-1-(1,3,3- trimethylpiperidin-4-yl)urea, GA35

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-hydroxybenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA36

1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)-1-(3- (hydroxymethyl)-1,3-dimethylpiperidin-4-yl)urea, GA37

1-benzyl-3-(1-(2,3- dihydroxyphenyl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA38

3-((R)-1-(2,3- dichlorophenyl)ethyl)-1-(3-(2-hydroxyethoxy)benzyl)-1-(1,3,3- trimethylpiperidin-4-yl)urea, GA39

3-(1-(2,3-difluoro-4- methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA40

3-(1-(2,3-difluoro-4- hydroxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA41

4-(1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)ureido)-1,3-dimethylpiperidine-3-carboxylic acid, GA42

ethyl 4-(3-(1-(2,3- dichlorophenyl)ethyl)-1- methylureido)-1,3-dimethylpiperidine-3-carboxylate, GA43

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-(hydroxymethyl)-1,3-dimethylpiperidin-4-yl)-1- methylurea, GA44

4-(3-(1-(2,3-dichlorophenyl)ethyl)- 1-methylureido)-1,3,3-trimethylpiperidine 1-oxide, GA45

3-(1-(benzo[d][1,3]dioxol-5- yl)ethyl)-1-benzyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA46

1-ethyl-1-(1-methylpiperidin-4-yl)- 3-(1-(naphthalen-1-yl)ethyl)urea,GA47

3-(1-(4-methoxynaphthalen-1- yl)ethyl)-1-methyl-methylpiperidin-4-yl)urea, GA48

3-(2-hydroxy-1-(naphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA49

3-(2-hydroxy-1-(4- methoxynaphthalen-1-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA50

1-(1-methylpiperidin-4-yl)-3-(1- (naphthalen-1-yl)ethyl)-1-(pyridin-3-ylmethyl)urea, GA51

1-cyclopentyl-1-(1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA52

1-methyl-3-(1-(naphthalen-1- yl)ethyl)-1-(piperidin-4-yl)urea, GA53

1-(1-acetylpiperidin-4-yl)-1- methyl-3-(1-(naphthalen-1- yl)ethyl)urea,GA54

1-methyl-1-(1- (methylsulfonyl)piperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA55

1-methyl-3-(1-(naphthalen-1- yl)ethyl)-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)urea, GA56

1-cyclohexyl-1-(1-methylpiperidin- 4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA57

1-(cyclohexylmethyl)-1-(1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA58

1-isopropyl-1-(1-methylpiperidin- 4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA59

1-(2-methoxyethyl)-1-(1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA60

1-(1-ethylpiperidin-4-yl)-1-methyl- 3-(1-(naphthalen-1-yl)ethyl)urea,GA61

1-ethyl-4-(1-methyl-3-(1- (naphthalen-1- yl)ethyl)ureido)piperidine1-oxide, GA62

1-(cyclopropylmethyl)-1-(1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA63

3-(1-(2-methoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA64

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(quinolin-4-yl)ethyl)urea,GA65

tert-butyl 4-(1-methyl-3-(1- (naphthalen-1-yl)ethyl)ureido)piperidine-1- carboxylate, GA66

1-(1-formylpiperidin-4-yl)-1- methyl-3-(1-(naphthalen-1- yl)ethyl)urea,GA67

3-(2-methoxy-1-(naphthalen-1- yl)ethyl)-1-methyl-methylpiperidin-4-yl)urea, GA68

3-(3-methoxy-1-(naphthalen-1- yl)propyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA69

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(naphthalen-1- yl)propyl)urea,GA70

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(quinolin-5-yl)ethyl)urea,GA71

1-methyl-1-(1-methylpiperidin-4- yl)-3-(2-(naphthalen-1-yl)propan-2-yl)urea, GA72

3-(1-(2-chloroquinolin-4-yl)ethyl)- 1-methyl-1-(1-methylpiperidin-4-yl)urea, GA73

(S)-1-(1-methylpiperidin-4-yl)-3- (1-(naphthalen-1-yl)ethyl)-1-(pyridin-3-ylmethyl)urea, GA74

(R)-1-(1-methylpiperidin-4-yl)-3- (1-(naphthalen-1-yl)ethyl)-1-(pyridin-3-ylmethyl)urea, GA75

1-isobutyl-1-(1-methylpiperidin-4- yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA76

1-(cyclobutylmethyl)-1-(1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA77

1-butyl-1-(1-methylpiperidin-4-yl)- 3-(1-(naphthalen-1-yl)ethyl)urea,GA78

3-(1-(2-methoxyquinolin-4- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA79

1-(1-methylpiperidin-4-yl)-3-(1- (naphthalen-1-yl)ethyl)-1-(pyridin-2-ylmethyl)urea, GA80

1-(1-methylpiperidin-4-yl)-3-(1- (naphthalen-1-yl)ethyl)-1-(pyridin-4-ylmethyl)urea, GA81

(S)-1-ethyl-3-(1-(2- methoxyquinolin-4-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA82

(R)-1-ethyl-1-(1-methylpiperidin- 4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA83

3-(2-hydroxy-1-(4- methoxynaphthalen-1-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA84

3-(2-hydroxy-1-(naphthalen-1- yl)ethyl)-1-(1-methylpiperidin-4-yl)-1-(pyridin-3-ylmethyl)urea, GA85

3-(2-methoxy-1-(4- methoxynaphthalen-1-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA86

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-hydroxybenzyl)-1-(1-methylpiperidin-4-yl)urea, GA87

1-benzyl-1-(1,3-dimethylpiperidin- 4-yl)-3-((R)-1-(naphthalen-1-yl)ethyl)urea, GA88

1-(1,3-dimethylpiperidin-4-yl)-1- methyl-3-((R)-1-(naphthalen-1-yl)ethyl)urea, GA89

3-(1-(4-methoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA90

(R)-3-(1-(4-methoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA91

(S)-3-(1-(4-methoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA92

3-(1-(4,8-dimethoxynaphthalen-1- yl)ethyl)-1-methyl-methylpiperidin-4-yl)urea, GA93

3-(1-(4- (methoxymethoxy)naphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA94

3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA95

(R)-3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA96

(S)-3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA97

3-(1-(2,3-dichlorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4-yl)urea, GA98

1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA99

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea, GA100

1-(2-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA101

3-(1-(3,5-difluorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4-yl)urea, GA102

3-(1-(2-chlorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4- yl)urea,GA103

3-(1-(3-fluorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4- yl)urea,GA104

3-(1-(4-chlorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4- yl)urea,GA105

3-(1-(2,4-difluorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4-yl)urea, GA106

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(o-tolyl)ethyl)urea, GA107

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(4-(methylsulfonyl)phenyl)ethyl)urea, GA108

1-(cyclohexylmethyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA109

1-(cyclopropylmethyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA110

3-(1-(2,3-dichlorophenyl)ethyl)-1- ethyl-1-(1-methylpiperidin-4-yl)urea, GA111

3-(1-(2,3-dichlorophenyl)ethyl)-1- (1-methylpiperidin-4-yl)-1-(pyridin-3-ylmethyl)urea, GA112

3-(1-(3-chlorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4- yl)urea,GA113

1-benzyl-3-(1-(3- chlorophenyl)ethyl)-1-(1- methylpiperidin-4-yl)urea,GA114

1-(3-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA115

3-(1-(2,3-dichlorophenyl)ethyl)-1- (2-methoxybenzyl)-1-(1-methylpiperidin-4-yl)urea, GA116

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-methoxybenzyl)-1-(1-methylpiperidin-4-yl)urea, GA117

3-(1-(2,3-dichlorophenyl)ethyl)-1- (4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea, GA118

3-(1-(2,3-dichlorophenyl)ethyl)-1- (2-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea, GA119

1-(4-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA120

3-(1-(3,4-dichlorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4-yl)urea, GA121

3-(1-(2,3-dichlorophenyl)ethyl)-1- (4-methoxybenzyl)-1-(1-methylpiperidin-4-yl)urea, GA122

3-(1-(2,3-dichlorophenyl)propyl)- 1-ethyl-1-(1-methylpiperidin-4-yl)urea, GA123

1-(cyclohexylmethyl)-3-(1-(2,3- dichlorophenyl)propyl)-1-(1-methylpiperidin-4-yl)urea, GA124

3-(1-(2,3-difluorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4-yl)urea, GA125

1-benzyl-3-(1-(2,3- difluorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA126

1-(cyclohexylmethyl)-3-(1-(2,3- difluorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA127

(R)-3-(1-(2,3- dichlorophenyl)ethyl)-1-ethyl-1-(1-methylpiperidin-4-yl)urea, GA128

1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1,3-dimethylpiperidin-4-yl)urea, GA129

3-(1-(2,3-dichlorophenyl)ethyl)-1- (1,3-dimethylpiperidin-4-yl)-1-methylurea, GA130

(S)-3-(1-(2,3- dichlorophenyl)ethyl)-1-ethyl-1-(1-methylpiperidin-4-yl)urea, GA131

(R)-3-(1-(2,3- dichlorophenyl)ethyl)-1-ethyl-1-(1-methylpiperidin-4-yl)urea, GA132

3-(1-(2,3-dichlorophenyl)ethyl)-1- ethyl-1-(1-methylpiperidin-4-yl)urea, GA133

3-((R)-1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-(1,3-dimethylpiperidin-4-yl)-1-(3- methoxybenzyl)urea, GA134

3-((S)-1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-(1,3-dimethylpiperidin-4-yl)-1-(3- methoxybenzyl)urea, GA135

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-(1,3-dimethylpiperidin-4-yl)-1-(3- methoxybenzyl)urea, GA136

3-(1-(2,3-difluorophenyl)ethyl)-1- (1,3-dimethylpiperidin-4-yl)-1-(3-methoxybenzyl)urea, GA137

3-(1-(2,3-dichlorophenyl)ethyl)-1- (4-(hydroxymethyl)benzyl)-1-(1-methylpiperidin-4-yl)urea, GA138

methyl 4-((3-(1-(2,3- dichlorophenyl)ethyl)-1-(1- methylpiperidin-4-yl)ureido)methyl)benzoate, GA139

3-(2-cyclopropyl-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA140

3-(1-(2,3-dichlorophenyl)-2- hydroxyethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA141

(R)-1-(2-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA142

(S)-1-(2-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA143

1-(2-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA144

3-(1-(2,3-dimethoxyphenyl)ethyl)- 1-methyl-1-(1-methylpiperidin-4-yl)urea, GA145

3-(1-(2,3-difluoro-4- methoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA146

3-(1-(2,3-dichlorophenyl)-2- methoxyethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA147

N-(2,3-dichloro-4-(1-(3-methyl-3- (1-methylpiperidin-4-yl)ureido)ethyl)phenyl)acetamide, GA148

3-(1-(4-amino-2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA149

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA150

1-ethyl-1-(1-methylpiperidin-4-yl)- 3-(1-(naphthalen-1-yl)-3-(3-(pyridin-3- yloxy)phenyl)propyl)urea, GA151

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(naphthalen-1-yl)-3-(pyridin-3-yl)propyl)urea, GA152

1-methyl-1-(1-methylpiperidin-4- yl)-3-(3-morpholino-1-(naphthalen-1-yl)propyl)urea, GA153

1-ethyl-3-(3-(3-methoxyphenyl)-1- (naphthalen-1-yl)propyl)-1-(1-methylpiperidin-4-yl)urea, GA154

3-(3-(3-(benzyloxy)phenyl)-1- (naphthalen-1-yl)propyl)-1-ethyl-1-(1-methylpiperidin-4-yl)urea, GA155

1-ethyl-1-(1-methylpiperidin-4-yl)- 3-(1-(naphthalen-1-yl)-3-(pyridin-3-yl)propyl)urea, GA156

3-(3-(3-(benzyloxy)phenyl)-1- (naphthalen-1-yl)propyl)-1-(1-methylpiperidin-4-yl)-1-(pyridin-3- ylmethyl)urea, GA157

3-(3-(3-(benzyloxy)phenyl)-1-(2,3- dichlorophenyl)propyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA158

3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA159

3-(2-(benzylamino)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA160

3-(1-(2,3-dichlorophenyl)-2-((3- (hydroxymethyl)benzyl)oxy)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA161

3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-(2- chlorobenzyl)-1-(1-methylpiperidin-4-yl)urea, GA162

3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-(4-(hydroxymethyl)benzyl)-1-(1- methylpiperidin-4-yl)urea, GA163

3-(1-(2,3-dichlorophenyl)-2-((4- methoxybenzyl)oxy)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA164

3-(1-(2,3-dichlorophenyl)-2- (pyridin-4-ylmethoxy)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA165

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methoxy-1-(1-methylpiperidin-4-yl)urea, GA166

(S)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methoxy-1-(1-methylpiperidin-4-yl)urea, GA167

(R)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methoxy-1-(1-methylpiperidin-4-yl)urea, GA168

1-hydroxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA169

(R)-1-hydroxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA170

(S)-1-hydroxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA171

3-(1-(2,3-dichlorophenyl)ethyl)-1- methoxy-1-(1-methylpiperidin-4-yl)urea, GA172

(R)-3-(1-(2,3- dichlorophenyl)ethyl)-1-methoxy-1-(1-methylpiperidin-4-yl)urea, GA173

(S)-3-(1-(2,3- dichlorophenyl)ethyl)-1-methoxy-1-(1-methylpiperidin-4-yl)urea, GA174

1-methoxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA175

(R)-1-methoxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA176

(S)-1-methoxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA177

3-(1-(2,3-dichlorophenyl)ethyl)-1- hydroxy-1-(1-methylpiperidin-4-yl)urea, GA178

(R)-3-(1-(2,3- dichlorophenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, GA179

(S)-3-(1-(2,3- dichlorophenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, GA180

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, G181

(R)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, GA182

(S)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, GA183

3-(1-(2,3-dichloro-4- (dimethylamino)phenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA184

3-(1-(4-((4- methoxybenzyl)oxy)naphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, G185

3-(1-(4-hydroxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA186

3-(1-(4,5-dimethoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA187

3-(1-(2,3-dichlorophenyl)-2- (pyridin-3-ylmethoxy)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA188

3-(1-(4-chlorobcnzo[d][1,3]dioxol- 5-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA189

3-(1-(2-chloro-3,4- dimethoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA190

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(2,3,4-trichlorophenyl)ethyl)urea, GA191

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(4-(pyridin-4-ylmethoxy)naphthalen-1- yl)ethyl)urea, GA192

3-(1-(6-chloro-[1,1′-biphenyl]-2- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA193

3-(1-(3-chloro-2-(pyridin-4- yl)phenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA194

3-(1-(2,3-dichloro-4- methylphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA195

3-(1-(3-chloro-2- methylphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA196

3-(1-(2,3-dichlorophenyl)-2-((4- (hydroxymethyl)benzyl)oxy)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA197

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA198

(R)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA199

(S)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA200

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA201

3-((R)-1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA202

3-((S)-1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, and GA203

3-(1-(4-(2- (benzyloxy)ethoxy)naphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea.1. Isomers

When an asymmetric center is present in a compound of formula (I),hereinafter referred to as the disclosed compounds, the compound mayexist in the form of optical isomers (enantiomers). In some forms, thedisclosed compounds and compositions can comprise enantiomers andmixtures, including racemic mixtures of the compounds of formula (I). Insome forms, for compounds of formula (I) that contain more than oneasymmetric center, the disclosed compounds and compositions can comprisediastereomeric forms (individual diastereomers and mixtures thereof) ofcompounds. When a compound of formula (I) contains an alkenyl group ormoiety, geometric isomers may arise.

2. Tautomeric Forms

The disclosed compositions and compounds comprise the tautomeric formsof compounds of formula (I). Where structural isomers areinterconvertible via a low energy barrier, tautomeric isomerism(tautomerism) can occur. This can take the form of proton tautomerism incompounds of formula (I) containing, for example, an imino, keto, oroxime group, or so-called valence tautomerism in compounds which containan aromatic moiety. It follows that a single compound may exhibit morethan one type of isomerism. The various ratios of the tautomers in solidand liquid form are dependent on the various substituents on themolecule as well as the particular crystallization technique used toisolate a compound.

3. Salts

The disclosed compositions and compounds can be used in the form ofsalts derived from inorganic or organic acids. Depending on theparticular compound, a salt of the compound can be advantageous due toone or more of the salt's physical properties, such as enhancedpharmaceutical stability in differing temperatures and humidities, or adesirable solubility in water or oil. In some instances, a salt of acompound also can be used as an aid in the isolation, purification,and/or resolution of the compound.

Where a salt is intended to be administered to a patient (as opposed to,for example, being used in an in vitro context), the salt preferably ispharmaceutically acceptable. The term “pharmaceutically acceptable salt”refers to a salt prepared by combining a compound, such as the disclosedcompounds, with an acid whose anion, or a base whose cation, isgenerally considered suitable for human consumption. Pharmaceuticallyacceptable salts are particularly useful as products of the disclosedmethods because of their greater aqueous solubility relative to theparent compound. For use in medicine, the salts of the disclosedcompounds are non-toxic “pharmaceutically acceptable salts.” Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the disclosed compounds which are generally preparedby reacting the free base with a suitable organic or inorganic acid.

Suitable pharmaceutically acceptable acid addition salts of thedisclosed compounds, when possible include those derived from inorganicacids, such as hydrochloric, hydrobromic, hydrofluoric, boric,fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, andsulfuric acids, and organic acids such as acetic, benzenesulfonic,benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic,isothionic, lactic, lactobionic, maleic, malic, methanesulfonic,trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, andtrifluoroacetic acids. Suitable organic acids generally include, forexample, aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclylic, carboxylic, and sulfonic classes of organic acids.

Specific examples of suitable organic acids include acetate,trifluoroacetate, formate, propionate, succinate, glycolate, gluconate,digluconate, lactate, malate, tartaric acid, citrate, ascorbate,glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate,benzoate, anthranilic acid, mesylate, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid,galactarate, galacturonate, adipate, alginate, butyrate, camphorate,camphorsulfonate, cyclopentanepropionate, dodecylsulfate,glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate,2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate,picrate, pivalate, thiocyanate, tosylate, and undecanoate.

Furthermore, where the disclosed compounds carry an acidic moiety,suitable pharmaceutically acceptable salts thereof can include alkalimetal salts, e.g., sodium or potassium salts; alkaline earth metalsalts, e.g., copper, calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts. In someforms, base salts are formed from bases which form non-toxic salts,including aluminum, arginine, benzathine, choline, diethylamine,diolamine, glycine, lysine, meglumine, olamine, tromethamine and zincsalts.

Organic salts can be made from secondary, tertiary or quaternary aminesalts, such as tromethamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups canbe quaternized with agents such as lower alkyl (C1-C6) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), arylalkyl halides (e.g.,benzyl and phenethyl bromides), and others. In some forms, hemisalts ofacids and bases can also be formed, for example, hemisulphate andhemicalcium salts. The disclosed compounds can exist in both unsolvatedand solvated forms. A “solvate” as used herein is a nonaqueous solutionor dispersoid in which there is a noncovalent or easily dispersiblecombination between solvent and solute, or dispersion means and dispersephase.

4. Adducts

Also disclosed are so-called “adducts” of the disclosed compounds. Anrepresentive type of adduct can be Lewis acid adduct. Lewis acid is amolecular entity (and the corresponding chemical species) that is anelectron-pair acceptor and therefore able to react with a Lewis base toform a Lewis adduct, by sharing the electron pair furnished by the Lewisbase. An illustrative example is given by the reaction of trimethylboronand ammonia to give the adduct Me₃BNH₃. Typical Lewis acids are borontrihalides, for example, boron trifluoride. Thus, the disclosedcompounds encompass boron trihalides adduct, for example, borontrifluoride adduct.

5. Isotopes

Also disclosed are isotopically labeled compounds, which are identicalto those compounds recited in formula (I), but for the fact that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into disclosed compoundsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Disclosed compounds,prodrugs thereof, and pharmaceutically acceptable salts of saidcompounds or of said prodrugs which contain the aforementioned isotopesand/or other isotopes of other atoms are contemplated. Certainisotopically labeled disclosed compounds, for example those into whichradioactive isotopes such as ³H and ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i.e., ³H,and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withheavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically labeledcompounds of formula (I) (and other disclosed compounds) and prodrugsthereof can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples and Preparations below,by substituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

6. General Synthetic Schemes

The compounds of the formula (I) (and other disclosed compounds), ortheir pharmaceutically acceptable salts or adducts, can be prepared bythe methods as illustrated by examples described in the “Examples”section, together with synthetic methods known in the art of organicchemistry, or modifications and derivatisations that are familiar tothose of ordinary skill in the art. The starting materials used hereinare commercially available or can be prepared by routine methods knownin the art (such as those methods disclosed in standard reference bookssuch as the Compendium of Organic Synthesis Methods, Vol. I-VI(published by Wiley-Interscience)). Preferred methods include, but arenot limited to, those described below. During any of the followingsynthetic sequences it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This canbe achieved by means of conventional protecting groups, such as thosedescribed in T. W. Greene, Protective Groups in Organic Chemistry, JohnWiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Chemistry, John Wiley & Sons, 1991, T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999,and P. G. M. Wuts and T. W. Greene, Protective Groups in OrganicChemistry, John Wiley & Sons, 2006, which are hereby incorporated byreference. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

7. Definition of Terms

The term “alkyl” refers to a linear or branched-chain saturatedhydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbonby removal of a hydrogen) containing from one to twenty carbon atoms; inone embodiment from one to twelve carbon atoms; in another embodiment,from one to ten carbon atoms; in another embodiment, from one to sixcarbon atoms; and in another embodiment, from one to four carbon atoms.Examples of such substituents include methyl, ethyl, propyl (includingn-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyland tert-butyl), pentyl, iso-amyl, hexyl and the like.

The term “alkenyl” refers to a linear or branched-chain hydrocarbylsubstituent containing one or more double bonds and from two to twentycarbon atoms; in another embodiment, from two to twelve carbon atoms; inanother embodiment, from two to six carbon atoms; and in anotherembodiment, from two to four carbon atoms. Examples of alkenyl includeethenyl (also known as vinyl), allyl, propenyl (including 1-propenyl and2-propenyl) and butenyl (including 1-butenyl, 2-butenyl and 3-butenyl).The term “alkenyl” embraces substituents having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations.

The term “benzyl” refers to methyl radical substituted with phenyl,i.e., the following structure:

The term “carbocyclic ring” refers to a saturated cyclic, partiallysaturated cyclic, or aromatic ring containing from 3 to 14 carbon ringatoms (“ring atoms” are the atoms bound together to form the ring). Acarbocyclic ring typically contains from 3 to 10 carbon ring atoms.Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.A “carbocyclic ring system” alternatively may be 2 or 3 rings fusedtogether, such as naphthalenyl, tetrahydronaphthalenyl (also known as“tetralinyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl,anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”),fluorenyl, and decalinyl.

The term “heterocyclic ring” refers to a saturated cyclic, partiallysaturated cyclic, or aromatic ring containing from 3 to 14 ring atoms(“ring atoms” are the atoms bound together to form the ring), in whichat least one of the ring atoms is a heteroatom that is oxygen, nitrogen,or sulfur, with the remaining ring atoms being independently selectedfrom the group consisting of carbon, oxygen, nitrogen, and sulfur.

The term “cycloalkyl” refers to a saturated carbocyclic substituenthaving three to fourteen carbon atoms. In one embodiment, a cycloalkylsubstituent has three to ten carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “cycloalkyl” also includes substituents that are fused to aC₆-C₁₀ aromatic ring or to a 5-10-membered heteroaromatic ring, whereina group having such a fused cycloalkyl group as a substituent is boundto a carbon atom of the cycloalkyl group. When such a fused cycloalkylgroup is substituted with one or more substituents, the one or moresubstituents, unless otherwise specified, are each bound to a carbonatom of the cycloalkyl group. The fused C₆-C₁₀ aromatic ring or to a5-10-membered heteroaromatic ring may be optionally substituted withhalogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or ═O.

The term “cycloalkenyl” refers to a partially unsaturated carbocyclicsubstituent having three to fourteen carbon atoms, typically three toten carbon atoms. Examples of cycloalkenyl include cyclobutenyl,cyclopentenyl, and cyclohexenyl.

A cycloalkyl or cycloalkenyl may be a single ring, which typicallycontains from 3 to 6 ring atoms. Examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl,cyclohexenyl, cyclohexadienyl, and phenyl. Alternatively, 2 or 3 ringsmay be fused together, such as bicyclodecanyl and decalinyl.

The term “aryl” refers to an aromatic substituent containing one ring ortwo or three fused rings. The aryl substituent may have six to eighteencarbon atoms. As an example, the aryl substituent may have six tofourteen carbon atoms. The term “aryl” may refer to substituents such asphenyl, naphthyl and anthracenyl. The term “aryl” also includessubstituents such as phenyl, naphthyl and anthracenyl that are fused toa C₄-C₁₀ carbocyclic ring, such as a C₅ or a C₆ carbocyclic ring, or toa 4-10-membered heterocyclic ring, wherein a group having such a fusedaryl group as a substituent is bound to an aromatic carbon of the arylgroup. When such a fused aryl group is substituted with one moresubstituents, the one or more substituents, unless otherwise specified,are each bound to an aromatic carbon of the fused aryl group. The fusedC₄-C₁₀ carbocyclic or 4-10-membered heterocyclic ring may be optionallysubstituted with halogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or ═O.Examples of aryl groups include accordingly phenyl, naphthalenyl,tetrahydronaphthalenyl (also known as “tetralinyl”), indenyl,isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (alsoknown as “phenalenyl”), and fluorenyl.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (e.g., alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, etc.)is indicated by the prefix “C_(x)—C_(y)—,” wherein x is the minimum andy is the maximum number of carbon atoms in the substituent. Thus, forexample, “C₁-C₆-alkyl” refers to an alkyl substituent containing from 1to 6 carbon atoms. Illustrating further, C₃-C₆-cycloalkyl refers tosaturated cycloalkyl containing from 3 to 6 carbon ring atoms.

In some instances, the number of atoms in a cyclic substituentcontaining one or more heteroatoms (e.g., heteroaryl orheterocycloalkyl) is indicated by the prefix “X-Y-membered”, wherein xis the minimum and y is the maximum number of atoms forming the cyclicmoiety of the substituent. Thus, for example, 5-8-memberedheterocycloalkyl refers to a heterocycloalkyl containing from 5 to 8atoms, including one or more heteroatoms, in the cyclic moiety of theheterocycloalkyl.

The term “hydrogen” refers to hydrogen substituent, and may be depictedas —H.

The term “hydroxy” refers to —OH. When used in combination with anotherterm(s), the prefix “hydroxy” indicates that the substituent to whichthe prefix is attached is substituted with one or more hydroxysubstituents. Compounds bearing a carbon to which one or more hydroxysubstituents include, for example, alcohols, enols and phenol.

The term “hydroxyalkyl” refers to an alkyl that is substituted with atleast one hydroxy substituent. Examples of hydroxyalkyl includehydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.

The term “nitro” means —NO₂.

The term “cyano” (also referred to as “nitrile”)—CN, which also may bedepicted:

The term “carbonyl” means —C(O)—, which also may be depicted as:

The term “amino” refers to —NH₂.

The term “alkylamino” refers to an amino group, wherein at least onealkyl chain is bonded to the amino nitrogen in place of a hydrogen atom.Examples of alkylamino substituents include monoalkylamino such asmethylamino (exemplified by the formula —NH(CH₃)), which may also bedepicted:

and dialkylamino such as dimethylamino, (exemplified by the formula—N(CH₃)₂), which may also be depicted:

The term “aminocarbonyl” means —C(O)—NH₂, which also may be depicted as:

The term “halogen” refers to fluorine (which may be depicted as —F),chlorine (which may be depicted as —Cl), bromine (which may be depictedas —Br), or iodine (which may be depicted as —I). In one embodiment, thehalogen is chlorine. In another embodiment, the halogen is a fluorine.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogensubstituents. For example, haloalkyl refers to an alkyl that issubstituted with at least one halogen substituent. Where more than onehydrogen is replaced with halogens, the halogens may be the identical ordifferent. Examples of haloalkyls include chloromethyl, dichloromethyl,difluorochloromethyl, dichlorofluoromethyl, trichloromethyl,1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl,dichloropropyl, and heptafluoropropyl. Illustrating further,“haloalkoxy” refers to an alkoxy that is substituted with at least onehalogen substituent. Examples of haloalkoxy substituents includechloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy (also known as “perfluoromethyloxy”), and2,2,2-trifluoroethoxy. It should be recognized that if a substituent issubstituted by more than one halogen substituent, those halogensubstituents may be identical or different (unless otherwise stated).

The prefix “perhalo” indicates that each hydrogen substituent on thesubstituent to which the prefix is attached is replaced with anindependently selected halogen substituent. If all the halogensubstituents are identical, the prefix may identify the halogensubstituent. Thus, for example, the term “perfluoro” means that everyhydrogen substituent on the substituent to which the prefix is attachedis replaced with a fluorine substituent. To illustrate, the term“perfluoroalkyl” refers to an alkyl substituent wherein a fluorinesubstituent is in the place of each hydrogen substituent. Examples ofperfluoroalkyl substituents include trifluoromethyl (—CF₃),perfluorobutyl, perfluoroisopropyl, perfluorododecyl, andperfluorodecyl. To illustrate further, the term “perfluoroalkoxy” refersto an alkoxy substituent wherein each hydrogen substituent is replacedwith a fluorine substituent. Examples of perfluoroalkoxy substituentsinclude trifluoromethoxy (—O—CF₃), perfluorobutoxy, perfluoroisopropoxy,perfluorododecoxy, and perfluorodecoxy.

The term “oxo” refers to ═O.

The term “oxy” refers to an ether substituent, and may be depicted as—O—.

The term “alkoxy” refers to an alkyl linked to an oxygen, which may alsobe represented as —O—R, wherein the R represents the alkyl group.Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.

The term “alkylthio” means —S-alkyl. For example, “methylthio” is—S—CH₃. Other examples of alkylthio include ethylthio, propylthio,butylthio, and hexylthio.

The term “alkylcarbonyl” means —C(O)-alkyl. For example, “ethylcarbonyl”may be depicted as:

Examples of other alkylcarbonyl include methylcarbonyl, propylcarbonyl,butylcarbonyl, pentylcabonyl, and hexylcarbonyl.

The term “aminoalkylcarbonyl” means —C(O)-alkyl-NH₂. For example,“aminomethylcarbonyl” may be depicted as:

The term “alkoxycarbonyl” means —C(O)—O-alkyl. For example,“ethoxycarbonyl” may be depicted as:

Examples of other alkoxycarbonyl include methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, andhexyloxycarbonyl. In another embodiment, where the carbon atom of thecarbonyl is attached to a carbon atom of a second alkyl, the resultingfunctional group is an ester.

The terms “thio” and “thia” mean a divalent sulfur atom and such asubstituent may be depicted as —S—. For example, a thioether isrepresented as “alkyl-thio-alkyl” or, alternatively, alkyl-5-alkyl.

The term “thiol” refers to a sulfhydryl substituent, and may be depictedas —SH.

The term “thione” refers to ═S.

The term “sulfonyl” refers to —S(O)₂—, which also may be depicted as:Thus, for example, “alkyl-sulfonyl-alkyl” refers to alkyl-S(O)₂-alkyl.Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, andpropylsulfonyl.

The term “aminosulfonyl” means —S(O)₂—NH₂, which also may be depictedas:

The term “sulfinyl” or “sulfoxido” means —S(O)—, which also may bedepicted as:

Thus, for example, “alkylsulfinylalkyl” or “alkylsulfoxidoalkyl” refersto alkyl-S(O)-alkyl. Exemplary alkylsulfinyl groups includemethylsulfinyl, ethylsulfinyl, butylsulfinyl, and hexylsulfinyl.

The term “heterocycloalkyl” refers to a saturated or partially saturatedring structure containing a total of 3 to 14 ring atoms. At least one ofthe ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), withthe remaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur. A heterocycloalkylalternatively may comprise 2 or 3 rings fused together, wherein at leastone such ring contains a heteroatom as a ring atom (e.g., nitrogen,oxygen, or sulfur). In a group that has a heterocycloalkyl substituent,the ring atom of the heterocycloalkyl substituent that is bound to thegroup may be the at least one heteroatom, or it may be a ring carbonatom, where the ring carbon atom may be in the same ring as the at leastone heteroatom or where the ring carbon atom may be in a different ringfrom the at least one heteroatom. Similarly, if the heterocycloalkylsubstituent is in turn substituted with a group or substituent, thegroup or substituent may be bound to the at least one heteroatom, or itmay be bound to a ring carbon atom, where the ring carbon atom may be inthe same ring as the at least one heteroatom or where the ring carbonatom may be in a different ring from the at least one heteroatom.

The term “heterocycloalkyl” also includes substituents that are fused toa C₆-C₁₀ aromatic ring or to a 5-10-membered heteroaromatic ring,wherein a group having such a fused heterocycloalkyl group as asubstituent is bound to a heteroatom of the heterocyclocalkyl group orto a carbon atom of the heterocycloalkyl group. When such a fusedheterocycloalkyl group is substituted with one more substituents, theone or more substituents, unless otherwise specified, are each bound toa heteroatom of the heterocyclocalkyl group or to a carbon atom of theheterocycloalkyl group. The fused C₆-C₁₀ aromatic ring or to a5-10-membered heteroaromatic ring may be optionally substituted withhalogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or ═O.

The term “heteroaryl” refers to an aromatic ring structure containingfrom 5 to 14 ring atoms in which at least one of the ring atoms is aheteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ringatoms being independently selected from the group consisting of carbon,oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or 2 or3 fused rings. Examples of heteroaryl substituents include 6-memberedring substituents such as pyridyl, pyrazyl, pyrimidinyl, andpyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl,furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-,1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-memberedfused ring substituents such as benzothiofuranyl, isobenzothiofuranyl,benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-memberedfused rings such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,and 1,4-benzoxazinyl. In a group that has a heteroaryl substituent, thering atom of the heteroaryl substituent that is bound to the group maybe the at least one heteroatom, or it may be a ring carbon atom, wherethe ring carbon atom may be in the same ring as the at least oneheteroatom or where the ring carbon atom may be in a different ring fromthe at least one heteroatom. Similarly, if the heteroaryl substituent isin turn substituted with a group or substituent, the group orsubstituent may be bound to the at least one heteroatom, or it may bebound to a ring carbon atom, where the ring carbon atom may be in thesame ring as the at least one heteroatom or where the ring carbon atommay be in a different ring from the at least one heteroatom. The term“heteroaryl” also includes pyridyl N-oxides and groups containing apyridine N-oxide ring.

Examples of single-ring heteroaryls include furanyl, dihydrofuranyl,tetradydrofuranyl, thiophenyl (also known as “thiofuranyl”),dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl,pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl,imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl,tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl,isothiazolidinyl, thiaediazolyl, oxathiazolyl, oxadiazolyl (includingoxadiazolyl, 1,2,4-oxadiazolyl (also known as “azoximyl”),1,2,5-oxadiazolyl (also known as “furazanyl”), or 1,3,4-oxadiazolyl),oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl),dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl,1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl,oxathiolanyl, pyranyl (including 1,2-pyranyl or 1,4-pyranyl),dihydropyranyl, pyridinyl (also known as “azinyl”), piperidinyl,diazinyl (including pyridazinyl (also known as “1,2-diazinyl”),pyrimidinyl (also known as “1,3-diazinyl” or “pyrimidyl”), or pyrazinyl(also known as “1,4-diazinyl”)), piperazinyl, triazinyl (includings-triazinyl (also known as “1,3,5-triazinyl”), as-triazinyl (also known1,2,4-triazinyl), and v-triazinyl (also known as “1,2,3-triazinyl”)),oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (alsoknown as “pentoxazolyl”), 1,2,6-oxazinyl, or 1,4-oxazinyl), isoxazinyl(including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl,oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl),oxadiazinyl (including 1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl),morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

Examples of 2-fused-ring heteroaryls include, indolizinyl, pyrindinyl,pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl,pyridopyridinyl (including pyrido[3,4-b]-pyridinyl,pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl,indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl,phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl,benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl,benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl,benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl,benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, andtetrahydroisoquinolinyl.

Examples of 3-fused-ring heteroaryls or heterocycloalkyls include5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline,4,5-dihydroimidazo[4,5,1-hi]indole,4,5,6,7-tetrahydroimidazo[4,5,1-jk][1]benzazepine, and dibenzofuranyl.

Other examples of fused-ring heteroaryls include benzo-fused heteroarylssuch as indolyl, isoindolyl (also known as “isobenzazolyl” or“pseudoisoindolyl”), indoleninyl (also known as “pseudoindolyl”),isoindazolyl (also known as “benzpyrazolyl”), benzazinyl (includingquinolinyl (also known as “1-benzazinyl”) or isoquinolinyl (also knownas “2-benzazinyl”)), phthalazinyl, quinoxalinyl, quinazolinyl,benzodiazinyl (including cinnolinyl (also known as “1,2-benzodiazinyl”)or quinazolinyl (also known as “1,3-benzodiazinyl”)), benzopyranyl(including “chromanyl” or “isochromanyl”), benzothiopyranyl (also knownas “thiochromanyl”), benzoxazolyl, indoxazinyl (also known as“benzisoxazolyl”), anthranilyl, benzodioxolyl, benzodioxanyl,benzoxadiazolyl, benzofuranyl (also known as “coumaronyl”),isobenzofuranyl, benzothienyl (also known as “benzothiophenyl,”“thionaphthenyl,” or “benzothiofuranyl”), isobenzothienyl (also known as“isobenzothiophenyl,” “isothionaphthenyl,” or “isobenzothiofuranyl”),benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl,benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl,2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), benzisoxazinyl (including1,2-benzisoxazinyl or 1,4-benzisoxazinyl), tetrahydroisoquinolinyl,carbazolyl, xanthenyl, and acridinyl.

The term “heteroaryl” also includes substituents such as pyridyl andquinolinyl that are fused to a C₄-C₁₀ carbocyclic ring, such as a C₅ ora C₆ carbocyclic ring, or to a 4-10-membered heterocyclic ring, whereina group having such a fused aryl group as a substituent is bound to anaromatic carbon of the heteroaryl group or to a heteroatom of theheteroaryl group. When such a fused heteroaryl group is substituted withone more substituents, the one or more substituents, unless otherwisespecified, are each bound to an aromatic carbon of the heteroaryl groupor to a heteroatom of the heteroaryl group. The fused C₄-C₁₀ carbocyclicor 4-10-membered heterocyclic ring may be optionally substituted withhalogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or ═O.

The term “ethylene” refers to the group —CH₂—CH₂—. The term “ethynelene”refers to the group —CH═CH—. The term “propylene” refers to the group—CH₂—CH₂—CH₂—. The term “butylene” refers to the group—CH₂—CH₂—CH₂—CH₂—. The term “methylenoxy” refers to the group —CH₂—O—.The term “methylenethioxy” refers to the group —CH₂—S—. The term“methylenamino” refers to the group —CH₂—N(H)—. The term “ethylenoxy”refers to the group —CH₂—CH₂—O—. The term “ethylenethioxy” refers to thegroup —CH₂—CH₂—S—. The term “ethylenamino” refers to the group—CH₂—CH₂—N(H)—.

A substituent is “substitutable” if it comprises at least one carbon,sulfur, oxygen or nitrogen atom that is bonded to one or more hydrogenatoms. Thus, for example, hydrogen, halogen, and cyano do not fallwithin this definition. If a substituent is described as being“substituted,” a non-hydrogen substituent is in the place of a hydrogensubstituent on a carbon, oxygen, sulfur or nitrogen of the substituent.Thus, for example, a substituted alkyl substituent is an alkylsubstituent wherein at least one non-hydrogen substituent is in theplace of a hydrogen substituent on the alkyl substituent. To illustrate,monofluoroalkyl is alkyl substituted with a fluoro substituent, anddifluoroalkyl is alkyl substituted with two fluoro substituents. Itshould be recognized that if there is more than one substitution on asubstituent, each non-hydrogen substituent may be identical or different(unless otherwise stated).

If a substituent is described as being “optionally substituted,” thesubstituent may be either (1) not substituted, or (2) substituted. If acarbon of a substituent is described as being optionally substitutedwith one or more of a list of substituents, one or more of the hydrogenson the carbon (to the extent there are any) may separately and/ortogether be replaced with an independently selected optionalsubstituent. If a nitrogen of a substituent is described as beingoptionally substituted with one or more of a list of substituents, oneor more of the hydrogens on the nitrogen (to the extent there are any)may each be replaced with an independently selected optionalsubstituent. One exemplary substituent may be depicted as —NR′R,″wherein R′ and R″ together with the nitrogen atom to which they areattached, may form a heterocyclic ring. The heterocyclic ring formedfrom R′ and R″ together with the nitrogen atom to which they areattached may be partially or fully saturated. In one embodiment, theheterocyclic ring consists of 3 to 7 atoms. In another embodiment, theheterocyclic ring is selected from the group consisting of pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, pyridyl andthiazolyl.

This specification uses the terms “substituent,” “radical,” and “group”interchangeably. If a group of substituents are collectively describedas being optionally substituted by one or more of a list ofsubstituents, the group may include: (1) unsubstitutable substituents,(2) substitutable substituents that are not substituted by the optionalsubstituents, and/or (3) substitutable substituents that are substitutedby one or more of the optional substituents. If a substituent isdescribed as being optionally substituted with up to a particular numberof non-hydrogen substituents, that substituent may be either (1) notsubstituted; or (2) substituted by up to that particular number ofnon-hydrogen substituents or by up to the maximum number ofsubstitutable positions on the substituent, whichever is less. Thus, forexample, if a substituent is described as a heteroaryl optionallysubstituted with up to 3 non-hydrogen substituents, then any heteroarylwith less than 3 substitutable positions would be optionally substitutedby up to only as many non-hydrogen substituents as the heteroaryl hassubstitutable positions. To illustrate, tetrazolyl (which has only onesubstitutable position) would be optionally substituted with up to onenon-hydrogen substituent. To illustrate further, if an amino nitrogen isdescribed as being optionally substituted with up to 2 non-hydrogensubstituents, then the nitrogen will be optionally substituted with upto 2 non-hydrogen substituents if the amino nitrogen is a primarynitrogen, whereas the amino nitrogen will be optionally substituted withup to only 1 non-hydrogen substituent if the amino nitrogen is asecondary nitrogen.

A prefix attached to a multi-moiety substituent only applies to thefirst moiety. To illustrate, the term “alkylcycloalkyl” contains twomoieties: alkyl and cycloalkyl. Thus, a C₁-C₆— prefix onC₁-C₆-alkylcycloalkyl means that the alkyl moiety of the alkylcycloalkylcontains from 1 to 6 carbon atoms; the C₁-C₆— prefix does not describethe cycloalkyl moiety. To illustrate further, the prefix “halo” onhaloalkoxyalkyl indicates that only the alkoxy moiety of the alkoxyalkylsubstituent is substituted with one or more halogen substituents. If thehalogen substitution may only occur on the alkyl moiety, the substituentwould be described as “alkoxyhaloalkyl.” If the halogen substitution mayoccur on both the alkyl moiety and the alkoxy moeity, the substituentwould be described as “haloalkoxyhaloalkyl.”

When a substituent is comprised of multiple moieties, unless otherwiseindicated, it is the intention for the final moiety to serve as thepoint of attachment to the remainder of the molecule. For example, in asubstituent A-B-C, moiety C is attached to the remainder of themolecule. In a substituent A-B-C-D, moiety D is attached to theremainder of the molecule. Similarly, in a substituentaminocarbonylmethyl, the methyl moiety is attached to the remainder ofthe molecule, where the substituent may also be depicted as

In a substituent trifluoromethylaminocarbonyl, the carbonyl moiety isattached to the remainder of the molecule, where the substituent mayalso be depicted as

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other. Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

B. Pharmaceutical Compositions

Pharmaceutical compositions for preventing and/or treating a subject arefurther provided comprising a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt or adductthereof, and one or more pharmaceutically acceptable excipients.

A “pharmaceutically acceptable” excipient is one that is notbiologically or otherwise undesirable, i.e., the material can beadministered to a subject without causing any undesirable biologicaleffects or interacting in a deleterious manner with any of the othercomponents of the pharmaceutical composition in which it is contained.The carrier can be selected to minimize any degradation of the activeingredient and to minimize any adverse side effects in the subject, aswould be well known to one of skill in the art. The carrier can be asolid, a liquid, or both.

The disclosed compounds can be administered by any suitable route,preferably in the form of a pharmaceutical composition adapted to such aroute, and in a dose effective for the treatment or prevention intended.The active compounds and compositions, for example, can be administeredorally, rectally, parenterally, ocularly, inhalationaly, or topically.In particular, administration can be epicutaneous, inhalational, enema,conjunctival, eye drops, ear drops, alveolar, nasal, intranasal,vaginal, intravaginal, transvaginal, ocular, intraocular, transocular,enteral, oral, intraoral, transoral, intestinal, rectal, intrarectal,transrectal, injection, infusion, intravenous, intraarterial,intramuscular, intracerebral, intraventricular, intracerebroventricular,intracardiac, subcutaneous, intraosseous, intradermal, intrathecal,intraperitoneal, intravesical, intracavernosal, intramedullar,intraocular, intracranial, transdermal, transmucosal, transnasal,inhalational, intracisternal, epidural, peridural, intravitreal, etc.

Suitable carriers and their formulations are described in Remington: TheScience and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, MackPublishing Company, Easton, Pa., 1995. Oral administration of a soliddose form can be, for example, presented in discrete units, such as hardor soft capsules, pills, cachets, lozenges, or tablets, each containinga predetermined amount of at least one of the disclosed compound orcompositions. In some forms, the oral administration can be in a powderor granule form. In some forms, the oral dose form is sub-lingual, suchas, for example, a lozenge. In such solid dosage forms, the compounds offormula I are ordinarily combined with one or more adjuvants. Suchcapsules or tablets can contain a controlled-release formulation. In thecase of capsules, tablets, and pills, the dosage forms also can comprisebuffering agents or can be prepared with enteric coatings.

In some forms, oral administration can be in a liquid dose form. Liquiddosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also can comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

In some forms, the disclosed compositions can comprise a parenteral doseform. “Parenteral administration” includes, for example, subcutaneousinjections, intravenous injections, intraperitoneally, intramuscularinjections, intrasternal injections, and infusion. Injectablepreparations (e.g., sterile injectable aqueous or oleaginoussuspensions) can be formulated according to the known art using suitabledispersing, wetting agents, and/or suspending agents. Typically, anappropriate amount of a pharmaceutically acceptable carrier is used inthe formulation to render the formulation isotonic. Examples of thepharmaceutically acceptable carrier include, but are not limited to,saline, Ringer's solution and dextrose solution. Other acceptableexcipients include, but are not limited to, thickeners, diluents,buffers, preservatives, surface active agents and the like.

In some forms, the disclosed compositions can comprise a topical doseform. “Topical administration” includes, for example, transdermaladministration, such as via transdermal patches or iontophoresisdevices, intraocular administration, or intranasal or inhalationadministration. Compositions for topical administration also include,for example, topical gels, sprays, ointments, and creams. A topicalformulation can include a compound which enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. When the compounds and compositions are administered by atransdermal device, administration will be accomplished using a patcheither of the reservoir and porous membrane type or of a solid matrixvariety. Typical formulations for this purpose include gels, hydrogels,lotions, solutions, creams, ointments, dusting powders, dressings,foams, films, skin patches, wafers, implants, sponges, fibres, bandagesand microemulsions. Liposomes can also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers can be incorporated—see, for example, J Pharm Sci, 88 (10),955-958, by Finnin and Morgan (October 1999).

Formulations suitable for topical administration to the eye include, forexample, eye drops wherein the disclosed compound or composition isdissolved or suspended in suitable carrier. A typical formulationsuitable for ocular or aural administration can be in the form of dropsof a micronised suspension or solution in isotonic, pH-adjusted, sterilesaline. Other formulations suitable for ocular and aural administrationinclude ointments, biodegradable (e.g. absorbable gel sponges, collagen)and non-biodegradable (e.g. silicone) implants, wafers, lenses andparticulate or vesicular systems, such as niosomes or liposomes. Apolymer such as crossed-linked polyacrylic acid, polyvinylalcohol,hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,can be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations can also be delivered by iontophoresis.

Other carrier materials and modes of administration known in thepharmaceutical art can also be used. The disclosed pharmaceuticalcompositions can be prepared by any of the well-known techniques ofpharmacy, such as effective formulation and administration procedures.The above considerations in regard to effective formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Liberman, et al., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds.,Handbook of Pharmaceutical Excipients (3^(rd) Ed.), AmericanPharmaceutical Association, Washington, 1999.

The disclosed compounds can be used, alone or in combination with othertherapeutic agents, in the treatment or prevention of various conditionsor disease states. The administration of two or more compounds “incombination” means that the two compounds are administered closelyenough in time that the presence of one alters the biological effects ofthe other. The two or more compounds can be administered simultaneously,concurrently or sequentially.

Disclosed are pharmaceutical compositions comprising an effective amountof a compound of the invention or a pharmaceutically accepted salt,solvate, clathrate, or prodrug thereof; and a pharmaceuticallyacceptable carrier or vehicle. These compositions may further compriseadditional agents. These compositions are useful for modulating theactivity of ghrelin receptor, thus to improve the prevention andtreatment of ghrelin receptor associated human diseases such as obesityand/or metabolic disorders.

Methods

All of the methods of the invention may be practiced with a compound ofthe invention alone, or in combination with other agents.

A. Treating

The above-described compounds and compositions are useful for theinhibition, reduction, prevention, and/or treatment of diseases whichare pathophysiologically modulated by the ghrelin receptor. Accordingly,in some forms, disclosed are methods of preventing and/or treatingdiseases which are pathophysiologically modulated by the ghrelinreceptor, comprising administering to a subject a therapeuticallyeffective amount of a compound of formula (I) as disclosed above, or apharmaceutically acceptable salt or adduct thereof.

Suitable subjects can include mammalian subjects. Mammals include, butare not limited to, canine, feline, bovine, caprine, equine, ovine,porcine, rodents, lagomorphs, primates, and the like, and encompassmammals in utero. In some forms, humans are the subjects. Human subjectscan be of either gender and at any stage of development.

Diseases modulated by the ghrelin receptor, and treatable by the methodsdisclosed herein, include obesity, overweight, eating disorder,diabetes, metabolic syndrome, cachexia resulting from cancer, congestiveheart failure, wasting due to ageing or AIDS, chronic liver failure,chronic obstructive pulmonary disease, gastrointestinal disease, gastricdisorder or substance abuse. Metabolic disorders treatable by theinstant methods include diabetes, Type I diabetes, Type II diabetes,inadequate glucose tolerance, insulin resistance, hyperglycemia,hyperinsulinemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia, obesity, aging, Syndrome X,atherosclerosis, heart disease, stroke, hypertension and peripheralvascular disease. Gastric disorders treatable by the instant methodsinclude post-operative ileus (POI), diabetic gastroparesis, and opioidinduced bowel dysfunction. Gastrointestinal diseases treatable by theinstant methods include irritable bowel syndrome, gastritis, acid refluxdisease, gastroparesis, and functional dyspepsia. Substance abusetreatable by the instant methods includes alcohol and drug abuse, andsaid drug includes amphetamines, barbiturates, benzodiazepines, cocaine,methaqualone, and opioids.

In some methods the compound of Formula (I) is a ghrelin receptormodulator. In some other methods the compound of Formula (I) is aghrelin receptor agonist. In some methods the compound of Formula (I) isa ghrelin receptor antagonist. In some methods, the compound of Formula(I) or a pharmaceutically acceptable salt or adduct thereof, isadministered by one or more routes selected from the group consisting ofrectal, buccal, sublingual, intravenous, subcutaneous, intradermal,transdermal, intraperitoneal, oral, eye drops, parenteral and topicaladministration. In some other methods, administration is accomplished byadministering an oral form of the compound of Formula (I) or apharmaceutically acceptable salt or adduct thereof

A therapeutically effective amount may vary widely depending on theseverity of the disease, the age and relative health of the subject, thepotency of the compound used and other factors. Therapeuticallyeffective amounts of compounds of Formula (I) may range fromapproximately 0.01 microgram per Kg (μg/Kg) body weight per day to about100 mg/Kg body weight per day, or from about 0.1 μg/Kg/day to about 10mg/Kg/day, or from about 1 μg/Kg/day to about 5 mg/Kg/day, or from about10 μg/Kg/day to about 5 mg/Kg/day, or from about 100 μg/Kg/day to about5 mg/Kg/day, or from about 500 μg/Kg/day to about 5 mg/Kg/day.

One of ordinary skill in the art of treating such diseases will be able,without undue experimentation and in reliance upon personal knowledgeand the disclosure of this application, to ascertain a therapeuticallyeffective amount of a compound of Formula I for a given disease. In someother forms, disclosed are methods of preventing and/or treating asubject, further comprising one or more therapeutic agents.

B. More Definitions of Terms

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon.

1. A, an, the

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a pharmaceuticalcarrier” includes mixtures of two or more such carriers, and the like.

2. Abbreviations

Abbreviations, which are well known to one of ordinary skill in the art,may be used (e.g., “h” or “hr” for hour or hours, “g” or “gm” forgram(s), “mL” for milliliters, and “rt” for room temperature, “nm” fornanometers, “M” for molar, and like abbreviations).

3. About

The term “about,” when used to modify the quantity of an ingredient in acomposition, concentrations, volumes, process temperature, process time,yields, flow rates, pressures, and like values, and ranges thereof,employed in describing the embodiments of the disclosure, refers tovariation in the numerical quantity that can occur, for example, throughtypical measuring and handling procedures used for making compounds,compositions, concentrates or use formulations; through inadvertenterror in these procedures; through differences in the manufacture,source, or purity of starting materials or ingredients used to carry outthe methods; and like considerations. The term “about” also encompassesamounts that differ due to aging of a composition or formulation with aparticular initial concentration or mixture, and amounts that differ dueto mixing or processing a composition or formulation with a particularinitial concentration or mixture. Whether modified by the term “about”the claims appended hereto include equivalents to these quantities.

4. Comprise

Throughout the description and claims of this specification, the word“comprise” and variations of the word, such as “comprising” and“comprises,” means “including but not limited to,” and is not intendedto exclude, for example, other additives, components, integers or steps.

5. Ghrelin Receptor Agonist

A ghrelin receptor agonist is any molecule that binds to and activatesthe Ghrelin receptor in the cells.

6. Ghrelin Receptor Antagonist

A ghrelin receptor antagonist is any molecule that binds to and inhibitsthe activity of Ghrelin receptor.

7. Pathophysiologically Mediated to Ghrelin Receptor

Something is “pathophysiologically mediated by the ghrelin receptor” ifthe ghrelin receptor is involved in the functional changes in bodyassociated with or resulting from disease or injury.

8. Obesity

Obesity is a medical condition in which excess body fat has accumulatedto the extent that it may have an adverse effect on health, leading toreduced life expectancy and/or increased health problems. Obesitytreatment includes inducing weight loss, reducing bodyweight, reducingfood intake, reducing appetite, increasing metabolic rate, reducing fatintake, reducing carbohydrate craving; or inducing satiety. Theobesity-related disorders herein are associated with, caused by, orresult from obesity. Examples of obesity-related disorders includeovereating, binge eating, and bulimia, hypertension, diabetes, elevatedplasma insulin concentrations and insulin resistance, dyslipidemias,hyperlipidemia, endometrial, breast, prostate and colon cancer,osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones,heart disease, abnormal heart rhythms and arrythmias, myocardialinfarction, congestive heart failure, coronary heart disease, suddendeath, stroke, polycystic ovary disease, craniopharyngioma, thePrader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects,normal variant short stature, Turner's syndrome, and other pathologicalconditions showing reduced metabolic activity or a decrease in restingenergy expenditure as a percentage of total fat-free mass, e.g, childrenwith acute lymphoblastic leukemia. Further examples of obesity-relateddisorders are metabolic syndrome, insulin resistance syndrome, sexualand reproductive dysfunction, such as infertility, hypogonadism in malesand hirsutism in females, gastrointestinal motility disorders, such asobesity-related gastro-esophageal reflux, respiratory disorders, such asobesity-hypoventilation syndrome (Pickwickian syndrome), cardiovasculardisorders, inflammation, such as systemic inflammation of thevasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia,lower back pain, gallbladder disease, gout, and kidney cancer, nicotineaddiction, substance addiction and alcoholism. The compositions of thepresent invention are also useful for reducing the risk of secondaryoutcomes of obesity, such as reducing the risk of left ventricularhypertrophy.

9. Metabolic Disorder

A metabolic disorder is a disorder of metabolism, such as diabetes, TypeI diabetes, Type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperinsulinemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity,aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertensionand peripheral vascular disease.

10. Congestive Heart Failure

Congestive heart failure (CHF) is a condition in which the heart'sfunction as a pump to deliver oxygen rich blood to the body isinadequate to meet the body's needs. Congestive heart failure can becaused by diseases that weaken the heart muscle, or diseases that causestiffening of the heart muscles, or diseases that increase oxygen demandby the body tissue beyond the capability of the heart to deliver. Manydiseases can impair the pumping action of the ventricles. For example,the muscles of the ventricles can be weakened by heart attacks orinfections (myocarditis). The diminished pumping ability of theventricles due to muscle weakening is called systolic dysfunction. Aftereach ventricular contraction (systole) the ventricle muscles need torelax to allow blood from the atria to fill the ventricles. Thisrelaxation of the ventricles is called diastole. Diseases such ashemochromatosis or amyloidosis can cause stiffening of the heart muscleand impair the ventricles' capacity to relax and fill; this is referredto as diastolic dysfunction. The most common cause of this islongstanding high blood pressure resulting in a thickened(hypertrophied) heart. Additionally, in some patients, although thepumping action and filling capacity of the heart may be normal,abnormally high oxygen demand by the body's tissues (for example, withhyperthyroidism) may make it difficult for the heart to supply anadequate blood flow (called high output heart failure). In some patientsone or more of these factors can be present to cause congestive heartfailure. Congestive heart failure can affect many organs of the body.For example, the weakened heart muscles may not be able to supply enoughblood to the kidneys, which then begin to lose their normal ability toexcrete salt (sodium) and water. This diminished kidney function cancause to body to retain more fluid. The lungs may become congested withfluid (pulmonary edema) and the person's ability to exercise isdecreased. Fluid may likewise accumulate in the liver, thereby impairingits ability to rid the body of toxins and produce essential proteins.The intestines may become less efficient in absorbing nutrients andmedicines. Over time, untreated, worsening congestive heart failure willaffect virtually every organ in the body.

11. Agonism Action

Agonism action refers to the binding of a molecule to a receptor thatleads to the activation of the receptor, thus triggering a cellularresponse similar to the cellular response for a known agonist for thereceptor.

12. Antagonism Action

Antagonism action refers to the binding of a molecule to a receptor thatleads to the inhibition of the receptor.

13. Modulate

To modulate, or forms thereof, means either increasing, decreasing, ormaintaining a cellular activity mediated through a cellular target. Itis understood that wherever one of these words is used it is alsodisclosed that it could be 1%, 5%, 10%, 20%, 50%, 100%, 500%, or 1000%increased from a control, or it could be 1%, 5%, 10%, 20%, 50%, or 100%decreased from a control.

14. Optional

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances where itdoes not.

15. Or

The word “or” or like terms as used herein means any one member of aparticular list and also includes any combination of members of thatlist.

16. Publications

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon.

17. Subject

As used throughout, by a “subject” is meant an individual. Thus, the“subject” can include, for example, domesticated animals, such as cats,dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.),laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.) mammals,non-human mammals, primates, non-human primates, rodents, birds,reptiles, amphibians, fish, and any other animal. The subject can be amammal such as a primate or a human. The subject can also be anon-human.

18. Treating

By “treating” or “treatment” is meant the medical management of apatient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. These terms include activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. These terms can mean that the symptoms of the underlyingdisease are reduced, and/or that one or more of the underlying cellular,physiological, or biochemical causes or mechanisms causing the symptomsare reduced. It is understood that reduced, as used in this context,means relative to the state of the disease, including the molecularstate of the disease, not just the physiological state of the disease.In certain situations a treatment can inadvertently cause harm. Inaddition, these terms include palliative treatment, that is, treatmentdesigned for the relief of symptoms rather than the curing of thedisease, pathological condition, or disorder; preventative treatment,that is, treatment directed to minimizing or partially or completelyinhibiting the development of the associated disease, pathologicalcondition, or disorder; and supportive treatment, that is, treatmentemployed to supplement another specific therapy directed toward theimprovement of the associated disease, pathological condition, ordisorder. These terms mean both treatment having a curing or alleviatingpurpose and treatment having a preventive purpose. The treatment can bemade either acutely or chronically. It is understood that treatment canmean a reduction or one or more symptoms or characteristics by at least5% 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.9%, 99.99%,100%, relative to a control. In the context of these terms, preventingrefers to the ability of a compound or composition (such as thedisclosed compounds and compositions) to prevent a disease identifiedherein in patients diagnosed as having the disease or who are at risk ofdeveloping such disease. In this context, preventing includes thedelaying the onset of the disease relative to a control. These terms donot require that the treatment in fact be effective to produce any ofthe intended results. It is enough that the results are intended.

19. Therapeutically Effective

The term “therapeutically effective” means that the amount of thecomposition used is of sufficient quantity to treat a subject as definedherein.

20. Toxicity

Toxicity is the degree to which a substance, molecule, is able to damagesomething, such as a cell, a tissue, an organ, or a whole organism, thathas been exposed to the substance or molecule. For example, the liver,or cells in the liver, hepatocytes, can be damaged by certainsubstances. The methods of the present invention are preferablynon-toxic.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary and arenot intended to limit the disclosure. Efforts have been made to ensureaccuracy with respect to numbers (e.g., amounts, temperature, etc.), butsome errors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

A. Example 1

1. Preparation of Compounds of Formula (I)

The following are examples of preparation of compounds of formula (I).This example is intended to be purely exemplary and is not intended tolimit the disclosure.

Synthesis of Compound 1 An Intermediate Compound

Step 1:

A solution of 1a (5 g, 25 mmol) in dry THF (10 mL) was cooled to 5° C.under nitrogen atmosphere. 60% NaH (2.4 g, 60 mmol) was added and theresulting mixture was stirred for 30 min. CH₃I (8.5 g, 60 mmol) was thenadded to the mixture and stirred at room temperature overnight. Thesolvent was removed under reduced pressure and the residue was dissolvedin ethyl acetate and washed with brine. The organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (silica, ethyl acetate/petroleumether 1:15, v:v) to provide compound 1b (2.9 g, 51% yield). ¹H-NMR(CDCl₃, 300 MHz): δ=3.74 (t, 2H), 3.41 (s, 2H), 2.50 (t, 2H), 1.44 (s,9H), 1.06 (s, 6H). LC-MS: 228 [M+1]⁺.

Step 2:

A solution of 1b (2.0 g, 8.8 mmol) in THF (30 mL) was treated with 1.5mL of conc. HCl at room temperature. The resulting mixture was heated at60° C. for 3 h, then cooled to room temperature. A white precipitateresulted and was collected by filtration and dried to obtain compound 1c(1.1 g, 78% yield) as HCl salt. This product was used in the next stepwithout further purification.

Step 3:

To a mixture of 1c (1.0 g, 6.1 mmol) and K₂CO₃ (2.5 g, 18.3 mmol) in dryCH₃CN (20 mL) was added CH₃I (0.95 g, 6.7 mmol) dropwise under N₂atmosphere. The mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure and the residue dissolved inethyl acetate, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography (silica,ethyl acetate/petroleum ether 1:10, v:v) to provide compound 1d (0.69 g,81% yield). ¹H-NMR (CDCl₃, 300 MHz): δ=2.65 (t, 2H), 2.50 (t, 2H), 2.38(s, 2H), 2.32 (s, 3H), 1.14 (s, 6H). LC-MS: 142 [M+1]⁺.

Step 4:

A mixture of 1d (0.5 g, 3.5 mmol) and methyl amine (30% in MeOH, 5 mL)was hydrogenated (50 psi, 60° C.) in the presence of 5% Pd/C (50 mg) inMeOH (5 mL). After cooling, the reaction mixture was filtered, thesolvent evaporated under reduced pressure and the residue purified bycolumn chromatography (silica, MeOH/CH₂Cl₂ 1:15, v:v) to provideCompound 1 (0.21 g, 39% yield). ¹H-NMR (CDCl₃, 300 MHz): δ=2.65 (t, 2H),2.56 (d, 3H), 2.51 (t, 2H), 2.38 (s, 2H), 2.32 (s, 3H), 1.14 (s, 6H).LC-MS: 157 [M+1]⁺.

Synthesis of Compound 2 An Intermediate Compound

Step 1:

To a solution of AlCl₃ (800 mg, 6 mmol) in dry CH₂Cl₂ (12 mL) was addedacyl chloride (236 mg, 3 mmol) at 0° C. under N₂. The mixture wasstirred for 10 min at room temperature, then compound 2a was added (474mg, 3 mmol) and the resulting mixture stirred at room temperatureovernight. Following water quench, the organic phase was separated,dried with anhydrous Na₂SO₄ and concentrated. The residue was purifiedby column chromatography (silica, ethyl acetate/petroleum ether 1:15,v:v) to provide compound 2b (338 mg, 56% yield) as a white solid. ¹H-NMR(CDCl₃, 300 MHz): δ=9.01-9.96 (m, 1H), 8.32-8.35 (m, 1H), 8.03 (d, 1H),7.63-7.65 (m, 1H), 7.53-7.58 (m, 1H), 6.79 (d, 1H), 4.07 (s, 3H), 2.72(s, 3H). LC-MS: 201 [M+1]⁺.

Step 2:

To a solution of compound 2b (167 mg, 0.84 mmol) in MeOH (5 mL) at 0° C.was added NaBH₄ (127 mg, 3.34 mmol). The mixture was stirred at roomtemperature for 2 h then the reaction was quenched with water. Thereaction mixture was concentrated and partitioned between ethyl acetateand water. The organic phase was separated, dried with anhydrous Na₂SO₄and concentrated under reduce pressure to give 2c (170 mg, 100% yield)which was used in the next step without further purification. ¹H-NMR(CDCl₃, 300 MHz): δ=8.30-8.33 (m, 1H). 8.12-8.16 (m, 1H), 7.52-7.58 (m,3H), 6.80 (d, 1H), 5.59 (q, 1H), 4.00 (s, 3H), 1.66 (d, 3H). LC-MS: 203[M+1]⁺.

Step 3:

To a mixture of 2c (170 mg, 0.84 mmol), phthalimide (186 mg, 1.26 mmol)and PPh₃ (441 mg, 1.68 mmol) in dry THF (12 mL) was added DIAD (340 mg,1.68 mmol) at room temperature under N₂. The mixture was stirred at roomtemperature overnight and then concentrated. The residue was purified bycolumn chromatography (silica, ethyl acetate/petroleum ether 1:15, v:v)to provide compound 2d (113 mg, 41% yield). ¹H-NMR (CDCl₃, 300 MHz):δ=8.28-8.30 (m, 1H), 8.12 (d, 1H), 7.92 (d, 1H), 7.74-7.76 (m, 2H),7.65-7.68 (m, 2H), 7.52-7.56 (m, 1H), 7.43-7.45 (m, 1H), 6.87 (d, 1H),6.24 (q, 1H), 4.01 (s, 3H), 2.01 (d, 3H).

Step 4:

A solution of compound 2d (113 mg, 0.34 mmol) in MeOH (4 mL) was treatedwith hydrazine hydrate (98%, 68 mg, 1.36 mmol) under reflux for 2 h. Themixture was then cooled and concentrated. The residue was partitionedbetween CH₂Cl₂ and water. The organic phase was separated, dried withanhydrous Na₂SO₄ and concentrated to give Compound 2 (65 mg, 95% yield)as a yellow oil. ¹H-NMR (CDCl₃, 300 MHz): δ=8.32 (d, 1H), 8.08 (d, 1H),7.46-7.56 (m, 3H), 6.79 (d, 1H), 4.86 (q, 1H), 3.96 (s, 3H), 1.64 (s,2H), 1.52 (d, 3H). LC-MS: 202 [M+1]⁺.

Synthesis of Compound 3 An Intermediate Compound

Compound 3 was prepared using a synthetic procedure analogous to that ofCompound 2 to yield the target compound as a light-yellow oil (8.6 g,55% yield). ¹H NMR (CDCl₃, 300 MHz,): δ=7.42 (d, 1H), 6.87 (d, 1H), 4.52(q, 1H), 3.90 (s, 3H), 1.66 (s, 2H), 1.36 (d, 3H). LC-MS: 220 [M+1]⁺.

Synthesis of Compound 4

Step 1:

To a solution of 4a (1 g, 5 mmol) in MeOH (50 mL) was added acetic acid(0.5 mL, 8.7 mmol), sodium acetate (0.5 g, 6 mmol) and hydroxylaminehydrochloride (340 mg, 5 mmol), followed by NaBH₃CN (640 mg, 10 mmol).The mixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure and the residue washed with aqueousNaHCO₃ solution and the mixture extracted with CH₂Cl₂ (3×30). Thecombined organic phases were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica, ethyl acetate/petroleum ether 1:1, v:v) toprovide compound 4b (650 mg, 60% yield). ¹H-NMR (CDCl₃, 300 MHz):δ=4.03-4.07 (m, 2H), 2.91-3.01 (m, 1H), 2.76-2.84 (m, 2H), 1.83-1.88 (m,2H), 1.41 (s, 9H), 1.23-1.35 (m, 2H). LC-MS: 217 [M+1]⁺.

Step 2:

To a solution of compound 2 (45 mg, 0.72 mmol) in CH₂Cl₂(30 mL) at 0° C.was added TEA (1.5 mL, 10.4 mmol) and triphosgene (210 mg, 0.72 mmol).The mixture was stirred for 15 min, then 4b (155 mg, 0.72 mmol) wasadded. The resulting mixture was warmed to room temperature and stirredfor 30 min. Following concentration, the residue was washed with anaqueous solution of NaHCO₃ and extracted with CH₂Cl₂. The combinedorganic phases were dried with Na₂SO₄ and concentrated to provide crudeurea 4c, which was used in the next step without further purification.LC-MS: 444 [M+1]⁺.

Step 3:

To a solution of 4c (300 mg 0.92 mmol) in MeOH (20 mL) at 0° C. wasadded anhydrous HCl in MeOH (2N, 10 mL). The mixture was stirred at roomtemperature for 2 h. After concentration, the residue was dissolved inMeOH (30 mL) and sodium acetate (0.5 g, 6 mmol), acetic acid (0.5 mL,8.7 mmol) and 38% formaldehyde solution (2 mL, 25 mmol) were added,followed by NaBH₃CN (87 mg, 1.3 mmol). The resulting mixture was stirredat room temperature overnight and then concentrated under reducedpressure. The residue was washed with saturated aqueous NaHCO₃ (40 mL)solution, and extracted with CH₂Cl₂ (3×50 mL). The combined organicphases were dried with anhydrous Na₂SO₄ and concentrated under reducedpressure to yield a residue that was purified by column chromatography(silica, MeOH/CH₂Cl₂ 1:20, v:v) to provide Compound 4 (130 mg, 50%yield) as a white solid. ¹H-NMR (300 MHz, CDCl₃): δ=8.26-8.29 (m, 1H);8.03-8.06 (m, 1H), 7.36-7.52 (m, 3H), 6.72-6.74 (d, 1H), 6.26-6.29 (d,1H), 5.64-5.69 (m, 1H), 4.06-4.08 (m, 1H), 3.98 (s, 3H), 2.89-2.93 (m,2H), 1.93-2.20 (m, 4H), 2.08 (s, 3H) 1.53-1.68 (m, 2H), 1.57 (d, 3H).LC-MS: 358 [M+1]

Synthesis of Compound 5

Step 1:

To a solution of 5a (5.65 g, 50 mmol) and methoxyamine (5 g, 60 mmol) inMeOH (150 mL) was added acetic acid (5 mL, 87.5 mmol), sodium acetate(5.0 g, 60 mmol), followed by NaBH₃CN (640 mg, 10 mmol). The mixture wasstirred at room temperature for 48 h, then quenched with aqueous sat.NaHCO₃ (add volume). The aqueous layer was extracted with CH₂Cl₂ (3×160mL). The combined organic phase was dried over anhydrous Na₂SO₄ andevaporated to provide product 5b (21% crude yield) as a colorless oil,which was used in the next step without further purification. LC-MS: 145[M+1]⁺.

Step 2:

To a solution of Compound 3 (250 mg, 1.14 mmol) in CH₂Cl₂(60 mL) at 0°C. was added TEA (3.5 ml, 25.21 mmol) and triphosgene (203 mg, 0.68mmol). The mixture was stirred for 15 min, then crude 5b (329 mg, 2.28mmol) was added. The resulting mixture was stirred for 30 min andevaporated. The residue was purified by column chromatography (silica,MeOH/CH₂Cl₂ 1:20, v:v) to afford Compound 5 (100 mg, 22% yield) as awhite solid. ¹H-NMR (CDCl₃, 300 MHz): δ=7.17 (d, 1H); 6.84 (d, 1H),6.21-6.30 (m, 1H), 5.16-5.24 (m, 1H), 4.00-4.16 (m, 1H), 3.89 (s, 3H),3.72 (s, 3H), 3.18-3.29 (m, 2H), 2.53 (s, 3H), 2.21-2.50 (m, 4H),1.69-1.90 (m, 2H), 1.50 (d, 3H). LC-MS: 390 [M+1]⁺.

Synthesis of Compound 6

An analogous procedure to the last step of the synthesis of Compound 5provided the target Compound 6 (120 mg, 61% yield) as a yellow solid.¹H-NMR (CDCl₃, 300 MHz): δ=8.14 (d, 1H); 7.91 (t, 1H), 7.78 (d, 1H),7.47-7.56 (m, 4H), 6.57 (d, 1H), 5.63-5.72 (m, 1H), 3.83-3.97 (m, 1H),3.16 (q, 2H), 2.75 (d, 2H), 2.12 (s, 3H), 1.84-1.91 (m, 2H), 1.55-1.66(m, 2H), 1.49 (d, 3H), 1.40-1.48 (m, 2H), 0.99 (t, 3H). LC-MS: 340[M+1]⁺.

Synthesis of Compound 7

Following an analogous synthetic procedure to the last step in thepreparation of Compound 5, compound 7 (140 mg, 91% yield) was obtainedas a yellow solid. ¹H-NMR (300 MHz, CDCl₃): δ=7.32-7.35 (m, 1H);7.16-7.23 (m, 2H), 5.22-5.36 (m, 1H), 4.82 (d, 1H), 4.04-4.17 (m, 1H),2.82-2.92 (m, 2H), 2.77 (s, 3H), 2.25 (s, 3H), 1.96-2.03 (m, 2H),1.61-1.74 (m, 4H), 1.46 (d, 3H). LC-MS: 344 [M+1]⁺.

Synthesis of Compound 8

Following an analogous synthetic procedure to the last step in thepreparation of Compound 5, compound 8 (101 mg, 28% yield) was obtainedas a yellow solid. ¹H-NMR (CDCl₃, 300 MHz): δ=8.30-8.32 (m, 1H), 8.09(t, 1H), 7.43-7.48 (m, 3H), 6.77 (d, 1H), 5.72-5.76 (m, 1H), 4.56 (t,1H), 4.36-4.38 (m, 1H), 4.00 (s, 3H), 3.12-3.15 (m, 2H), 2.64 (s, 3H),2.36-2.39 (m, 5H), 2.00-2.03 (m, 2H), 1.60-1.66 (m, 5H); LC-MS: 356[M+1]⁺.

Synthesis of Compound 9

Following an analogous synthetic procedure to the last step in thepreparation of Compound 5, compound 9 (100 mg, 64% yield) was obtainedas a white solid. ¹H-NMR (CDCl₃, 300 MHz): δ=7.40-7.25 (m, 6H);7.06-7.01 (t, 1H), 6.75-6.72 (m, 1H), 5.28-5.23 (m, 1H), 4.70-4.68 (d,1H), 4.40-4.38 (m, 3H), 2.87-2.83 (m, 2H), 2.23 (s, 3H), 2.05-2.01 (m,2H), 1.74-1.61 (m, 4H), 1.22-1.19 (d, 3H). LC-MS: 420 [M+1]⁺.

Synthesis of Compound 10

Following an analogous synthetic procedure to the last step in thepreparation of Compound 5, compound 10 (176 mg, 76% yield) was obtainedas a white solid. ¹H-NMR (CDCl₃, 300 MHz): δ=7.28-7.37 (m, 2H);6.97-7.11 (m, 4H), 6.81-6.85 (m, 1H), 5.24-5.29 (m, 1H), 4.67-4.70 (m,1H), 4.30-4.47 (m, 3H), 2.90-2.98 (m, 2H), 2.16 (s, 3H), 2.10-2.21 (m,2H), 1.31-1.98 (m, 4H), 1.22 (d, 3H). LC-MS: 438 [M+1]⁺.

Synthesis of Compound 11

Following an analogous synthetic procedure to the last step in thepreparation of Compound 5, compound 11 (105 mg, 35% yield) was obtainedas a white solid. ¹H-NMR (CDCl₃, 300 MHz): δ=7.40-7.42 (m, 1H),7.29-7.31 (m, 1H), 7.25-7.27 (m, 3H), 7.05-7.10 (m, 1H), 6.89-6.92 (m,1H), 5.29-5.20 (m, 1H), 4.64 (d, 1H), 4.37-4.44 (m, 3H), 2.91-3.01 (m,2H), 2.32 (s, 3H), 2.17-2.23 (m, 2H), 1.65-1.82 (m, 4H), 1.33 (d, 3H).LC-MS: 454 [M+1]⁺.

Synthesis of Compound 12

Following an analogous synthetic procedure to the last step of thepreparation of Compound 5, compound 12 (120 mg, 46% yield) was obtainedas a white solid. ¹H-NMR (CDCl₃, 300 MHz): δ=7.32-7.36 (m, 1H);7.13-7.25 (m, 2H), 5.28-5.35 (m, 1H), 4.82-4.92 (m, 1H), 4.07-4.12 (m,1H), 2.94-3.00 (m, 1H), 2.85 (s, 3H), 2.40-2.47 (m, 1H), 2.22 (s, 3H),2.02-2.12 (m, 2H), 1.86-1.91 (m, 1H), 1.41-1.49 (m, 3H), 1.33-1.37 (m,1H), 1.07 (s, 3H), 0.82 (d, 3H). LC-MS: 372.1 [M+1]⁺.

Synthesis of Compound 13

Following an analogous synthetic procedure to the last step of thepreparation of Compound 5, compound 13 (70 mg, 36% yield) was obtainedas a light yellow solid. ¹H NMR (CDCl₃, 300 MHz): δ=8.28-8.31 (m, 1H),8.09 (d, 1H), 7.26-7.54 (m, 3H), 6.77 (d, 1H), 5.70-5.79 (m, 1H), 4.56(q, 1H), 4.16-4.28 (m, 1H), 4.00 (d, 3H), 2.96-3.00 (m, 1H), 2.67 (d,3H), 2.45 (d, 1H), 2.25-2.26 (m, 3H), 1.92-2.11 (m, 3H), 1.63-1.67 (m,3H), 1.40-1.48 (m, 1H), 1.05 (d, 3H), 0.90 (d, 3H); LC-MS: 384 [M+1]⁺

Synthesis of Compound 14

Step 1:

A mixture of 1d (0.5 g, 3.5 mmol) and benzyl amine (0.34 g, 3.19 mmol)in MeOH (30 mL) as stirred at room temperature for 3 h. Then NaBH₃CN(0.45 g, 7.0 mmol) was added and the reaction mixture was stirred atroom temperature overnight. The solvent was removed under reducepressure and the residue was dissolved in CH₂Cl₂ (50 mL). The mixturewas washed with 100 mL of brine (100 mL) and the organic phases driedover Na₂SO₄ and concentrated. The residue was purified by columnchromatograph (silica, MeOH:CH₂Cl₂1:20 to 1:10) to provide intermediate11a (0.2 g, 27% yield) as a light yellow oil. LC-MS: 234 [M+1]⁺.

Step 2:

This procedure is analogous to the final step of the synthesis ofCompound 5 and provided Compound 14 (80 mg, 20% yield) as a white solid.¹H-NMR (CDCl₃, 300 MHz,): δ=8.05-8.10 (m, 1H); 7.76-7.85 (m, 2H),7.64-7.66 (m, 2H), 6.33-7.79 (m, 7H), 5.73-5.79 (m, 1H), 4.31-4.67 (m,4H), 3.00-3.05 (m, 1H), 2.51-2.55 (m, 1H), 1.97-2.30 (m, 6H), 1.59-1.69(m, 1H), 1.29-1.33 (m, 3H), 0.95-1.15 (m, 6H). LC-MS: 430 [M+1]⁺.

Synthesis of Compound 15

Step 1:

Analogous to the preparation of 11a, compound 12b was obtained (2.1 g,63% yield) and used without further purification in the following step.LC-MS: 263 [M+1]⁺.

Step 2:

This step is analogous to the final step in the synthesis of Compound 5and provided Compound 15 (140 mg, 57% yield) as a white solid. ¹H-NMR(CDCl₃, 300 MHz): δ=7.22-7.31 (m, 2H); 7.09 (t, 1H), 6.79-6.95 (m, 4H),5.15-5.30 (m, 1H), 4.64-4.78 (m, 1H), 4.36-4.46 (m, 3H), 3.76-3.79 (d,3H), 3.94-3.96 (m, 1H), 2.39-2.42 (m, 1H), 2.19 (s, 3H), 1.98-2.05 (m,2H), 1.20-1.25 (m, 2H), 1.07-1.09 (m, 6H), 0.86-0.97 (m, 3H). LC-MS: 378[M+1]⁺.

Synthesis of Compound 16

Step 1:

The synthesis is similar to that of 11b and provided 13b (1.0 g, 46%yield) which was used in the following step without furtherpurification. LC-MS: 251 [M+1]⁺.

Step 2:

Compound 16 was synthesized using a procedure similar to the final stepin the preparation of Compound 5. Compound 16 was obtained as a whitesolid (195 mg, 49% yield). ¹H NMR (CDCl₃, 300 MHz): δ=7.25-7.40 (m, 6H);7.01-7.06 (m, 3H), 6.72-6.75 (m, 1H), 5.25-5.28 (m, 1H), 4.70 (d, 1H),4.38-4.40 (m, 3H), 2.83-2.87 (m, 2H), 2.24 (s, 3H), 2.01-2.05 (m, 2H),1.67-1.74 (m, 4H), 1.21 (d, 3H). LC-MS: 466 [M+1]⁺.

Synthesis of Compound 17

Step 1:

A mixture of 1b (2 g, 8.8 mmol) and methyl amine (30% in MeOH, 4 mL) washydrogenated (50 psi, 60° C.) in the presence of 5% Pd/C (2000 mg) inMeOH (25 mL) overnight. After cooling the mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography (silica, ethyl acetate/petroleum ether1:10, v:v) to provide compound 14a (1.0 g, 48% yield) as a light yellowoil. ¹H-NMR (CDCl₃, 300 MHz): δ=4.07-4.09 (m, 1H), 2.65 (t, 2H), 2.51(t, 2H), 2.43 (s, 3H), 2.38 (s, 2H), 1.41 (s, 9H), 1.14 (s, 6H). LC-MS:243 [M+1]⁺.

Step 2:

To a solution of Compound 3 (382 mg, 1.74 mmol) in CH₂Cl₂(50 mL) wasadded TEA (351 mg) and triphosgene (309 mg, 1.04 mmol). The mixture wasstirred for 15 min at 0° C., then 14a (407 mg, 1.92 mmol) was added. Theresulting mixture was stirred for 30 min at 0° C. and then concentratedunder reduced pressure. The residue was purified by columnchromatography (silica, MeOH/CH₂Cl₂ 1:20, v:v) to afford 14b (701 mg,82% yield). LC-MS: 488 [M+1]⁺.

Step 3:

To a solution of 14b (701 mg, 1.44 mmol) in THF (20 mL) was added conc.HCl (2 mL). The mixture was heated at 75° C. for 2 h, then the solventwas evaporated to obtain crude 14c (580 mg), which was used in next stepwithout further purification.

Step 4:

To the solution of crude 14c (580 mg) in MeOH (15 mL) was added aqueousformaldehyde (38%, 4 mL, 24 mmol,), sodium acetate (200 mg, 2.4 mmol)and acetic acid (2 mL, 26 mmol), followed by NaBH₃CN (135 mg, 2.9 mmol).The mixture was stirred at room temperature overnight, then concentratedunder reduced pressure. The residue was purified by columnchromatography (silica, MeOH/CH₂Cl₂ 1:20, v:v) to afford Compound 17(262 mg, 38% yield) as a white solid. ¹H-NMR (CDCl₃, 300 MHz):δ=7.17-7.22 (m, 1H); 6.81-6.84 (m, 1H), 5.21-5.26 (m, 1H), 4.81-4.92 (m,1H), 4.07-4.10 (m, 1H), 3.88-3.91 (m, 3H), 2.90-2.93 (m, 1H), 2.81-2.82(m, 3H), 2.38-2.42 (m, 1H), 2.21-2.22 (m, 3H), 1.85-2.05 (m, 4H),1.42-1.50 (m, 3H), 1.06-1.07 (m, 3H), 0.77-0.87 (m, 3H). LC-MS: 402[M+1]⁺.

Synthesis of Compound 18

Step 1:

To a solution of 15a (5.04 g, 26.8 mmol) in CH₂Cl₂ (80 mL) at 0° C. wasadded dropwise a solution of Br₂ (3.81 g, 24.1 mmol) in CH₂Cl₂. Thesolution was stirred at room temperature overnight. The reaction mixturewas washed with aqueous Na₂SO₃ solution, NaHCO₃ solution and watersuccessively. The organic phase was dried with anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicacolumn chromatography (silica, ethyl acetate/petroleum ether 1:60, v:v)to provide compound 15b (7.1 g, quantitative yield).

Step 2:

To a solution of compound 15b (3 g, 11.2 mmol) in MeOH (90 mL) at −20°C. to −10° C. was added NaBH₄ (936 mg, 24.5 mmol). The reaction mixturewas warmed up to room temperature and stirred for 1.5 h, then thesolvent was evaporated and the residue was partitioned between ethylacetate and water. The organic phase was separated, dried with anhydrousNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by column chromatography (silica, ethyl acetate/petroleum ether1:30, v:v) to provide compound 15c (2.2 g, 73% yield). ¹H-NMR (CDCl₃,300 MHz): δ=7.54-7.57 (m, 1H), 7.42-7.46 (m, 1H), 7.24-7.29 (m, 1H),5.29-5.34 (m, 1H), 3.81 (dd, 1H), 3.43 (dd, 1H), 2.84 (d, 1H).

Step 3:

To a solution of compound 15c (1.0 g, 3.72 mmol) in THF (100 mL) wasadded 1N KOH (5.6 mL, 5.58 mmol). The reaction was stirred at roomtemperature overnight. Ethyl acetate (100 mL) was added and the organicphase was washed with brine, dried with anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica, petroleum ether) to provide compound 15d (432mg, 62% yield). ¹H-NMR (CDCl₃, 300 MHz): δ=7.38-7.42 (m, 1H), 7.16-7.23(m, 2H), 4.19-5.21 (m, 1H), 3.20 (dd, 1H), 2.63 (dd, 1H).

Step 4:

Metallic sodium (11 mg, 0.53 mmol) was added to benzyl alcohol (2 mL) atroom temperature under N₂ and the mixture was stirred until sodium wascompletely dissolved. Compound 15d (100 mg, 0.53 mmol) was then added tothe solution, which was then stirred at 70° C. overnight. The reactionwas concentrated under reduced pressure and the residue was purified bycolumn chromatography (silica, ethyl acetate/petroleum ether 1:4, v:v)to provide compound 15e (44 mg, 28% yield). ¹H-NMR (CDCl₃, 300 MHz):δ=7.53-7.56 (m, 1H), 7.30-7.35 (m, 6H), 7.24-7.26 (m, 1H), 5.35 (q, 1H),4.61 (q, 2H), 3.78 (q, 1H), 3.38 (q, 1H), 3.00 (s, 1H).

Step 5:

To a solution of compound 15e (480 mg, 1.6 mmol), phthalimide (286 mg,1.9 mmol) and PPh₃ (629 mg, 2.4 mmol) in dry THF (20 mL) at roomtemperature under N₂, was added DIAD (485 mg, 2.4 mmol). The mixture wasstirred at room temperature overnight and then concentrated underreduced pressure. The residue was purified by column chromatography(silica, ethyl acetate/petroleum ether 1:30, v:v) to provide 15f (570mg, 83% yield). ¹H-NMR (CDCl₃, 300 MHz): δ=7.79-7.85 (m, 2H), 7.70-7.74(m, 2H), 7.58 (dd, 1H), 7.40 (dd, 1H), 7.24-7.27 (m, 5H), 7.19 (t, 1H),6.07 (dd, 1H), 4.59 (d, 2H), 4.46 (t, 1H), 4.00 (dd, 1H).

Step 6:

A solution of compound 15h (570 mg, 1.34 mmol) and hydrazine hydrate(98%) (270 mg, 5.36 mmol) in MeOH (10 mL) was heated under reflux for 2h. The mixture was then concentrated under reduced pressure, the residuewas dissolved in CH₂Cl₂ and washed with water. The aqueous phase wasback extracted with CH₂Cl₂ (3×30 mL) and the combined organic phaseswere dried with anhydrous Na₂SO₄ and concentrated to give 15g (350 mg,88% yield). LC-MS: 296 [M+1]⁺.

Step 7:

To a solution of 15g (350 mg, 1.19 mmol) in dry CH₂Cl₂ (10 mL) at roomtemperature under nitrogen was added triphosgene (353 mg, 1.19 mmol).The reaction was stirred at room temperature for 10 min, followed by theaddition of 7a (235 mg, 1.43 mmol). The reaction mixture was stirred atroom temperature for 1 h, then concentrated under reduced pressure. Theresidue was purified by column chromatography (silica, MeOH/CH₂Cl₂ 1:20,v:v) to provide compound Compound 18 (450 mg, 84% yield) as a whitesolid. ¹H-NMR (CDCl₃, 300 MHz): δ=7.28-7.36 (m, 8H), 5.43-5.48 (m, 2H),4.50 (q, 2H), 4.26-4.30 (m, 1H), 3.79 (q, 1H), 3.62 (q, 1H), 3.10 (t,2H), 2.81 (s, 3H), 2.43 (s, 3H), 2.30-2.36 (m, 2H), 2.10-2.17 (m, 2H),1.65-1.70 (m, 2H). LC-MS: 450 [M+1]¹.

Synthesis of Compound 19

A solution of 5a (115 mg, 0.584 mmol), 5b (98 mg, 0.596 mmol) and TEA(0.5 mL) in dry DCM (20 mL) was stirred at room temperature under N₂ for30 min. After the reaction was complete, water (10 mL) was added. Theorganic phase was separated, dried with Na₂SO₄ and concentrated. Theresidue was purified by column chromatography (silica, MeOH:DCM=1:20) toafford Compound 19 (108 mg, 57% yield). ¹H NMR (300 MHz, DMSO-d₆):δ=8.14 (d, 1H), 7.92 (t, 1H), 7.78 (d, 1H), 7.57-7.45 (m, 4H), 6.71 (d,1H), 5.71-5.60 (m, 1H), 4.16-4.08 (m, 1H), 3.17 (br, 2H); 2.72-2.61 (m,5H), 2.50 (s, 3H), 1.93-1.87 (m, 2H), 1.58-1.51 (m, 5H). LC-MS: 326[M+1]⁺

Synthesis of Compound 20

To a solution of 6a (100 mg, 0.584 mmol), TEA (1.5 mL) in dry DCM (20mL) was added triphosgene (104 mg, 0.350 mmol) at room temperature underN₂. The mixture was stirred at room temperature for 30 min, then 5b (98mg, 0.596 mmol) was added. The resulted mixture was stirred at roomtemperature for 30 min. Water (10 mL) was added and the organic phasewas separated, dried with Na₂SO₄ and concentrated. The residue waspurified by column chromatography (silica, MeOH:DCM=1:20) to provideCompound 20 (109 mg, 57% yield). ¹H NMR (300 MHz, DMSO-d₆): δ=8.13 (d,1H), 7.95 (t, 1H), 7.78 (d, 1H), 7.56-7.45 (m, 4H), 6.70-6.68 (d, 1H),5.70-5.61 (m, 1H), 4.02-3.94 (m, 1H), 2.93 (br, 2H), 2.70 (s, 3H), 2.27(s, 3H), 2.16 (br, 2H), 1.76-1.63 (m, 2H), 1.50-1.35 (m, 5H). LC-MS: 326[M+1]⁺.

2. Materials and Methods

i. Calcium FLIPR Assay

The intracellular calcium assay was carried out in a 384-well formatFLIPR™ (Molecular Device) HEK293/GHSR1a cell line. Cells were seeded 24hr prior to the experiments at an optimal density per well.Preincubation with selected calcium dye lasted for 30-60 min at roomtemperature or 37° C. Test compounds, dissolved in DMSO, were added atthe appropriate time and incubated for 15 min followed by the additionof ghrelin with FlexStation or FLIPR. Relative fluorescence wasmonitored by the FLIPR™ Molecular Device. EC₅₀ and IC₅₀ values wereestimated from dose-response data using GraphPad Prism software. Tocheck for GHSR-1a agonism the compound was added at t=20 sec. and thecalcium response was followed for 2 minutes. To check for GHSR-1aantagonism the compound and Ghrelin (10 nM) were added to the cells att=20 sec. and the calcium response was measured for 2 minutes. Thepotency of the antagonist was calculated by its ability to reduce theghrelin response. Dose-response curves were made for relevantantagonists.

ii. Evaluation of GHSR1a Antagonists on Food Intake Test in Mouse

Male C57BL/6J mice, 18-22 g body weight, were fasted overnight (16 hbefore compound administration) and placed in a regular light dark cycle(6:00-18:00 light/18:00-6:00 dark). After 1 wk acclimation, animals weresorted into two groups (n=6 each, 2 per cage) based on body weight.Animals in group one were be treated with vehicle and animals in group 2were treated with the test agent (n=6 for each group). The cumulativefood intake was evaluated at 1, 2, 4, 8 and 24 hrs after drug or vehicletreatment. Food intake was measured by subtracting uneaten food from theinitial premeasured food.

3. Results

The following table presents representative compounds of formula (I)with biological data including the ghrelin antagonist/agonist activityin vitro and mouse food intake results. The data clearly demonstratesthat compounds of formula (I) are ghrelin receptor modulators and areuseful in preventing and/or treating diseases associated with ghrelinreceptor, for example, obesity.

TABLE 1 Mouse Food IC₅₀ FLIPR EC₅₀ FLIPR Intake antagonist against (%inhibition. Activity Activity Doses as mg/kg Structure (μM) (μM/Emax)i.p.

0.021  0.009/1081 47% inhib. at 4 h, activity up to 8 hrs (30 mg/kg)

0.005  0.006/1268 NSE (30 mg/kg)

0.320   30/124 28% inhibition at 1 hr, activity up to 24 hrs (30 mg/kg)

0.120 0.009/138 NSE (10 mg/kg)

0.040  0.030/2316 NSE (10 mg/kg), 70% increase food intake at 1 hr,activity up to 24 hrs (30 mg/kg).

0.910  0.49/689 27% inhibition at to 24 hrs (10 mg/kg)

0.022 16.76/497 47% inhibition at 1 hr (10 mg/kg)

0.075   18.70/118.5 74% inhibition at 1 hr, activity up to 24 hrs (10mg/kg)

0.066  0.020/3945 47% inhibition at 1 hr (10 mg/kg)

0.065 30/NA 44% inhibition at 1 hr (10 mg/kg)

0.012   30/260 26% inhibition at 1 hr (10 mg/kg)

0.070    30/1573 NSE (3 mg/kg), 40% inhibition at 1 hr, activity up to 4hrs (10 mg/kg), 50% inhibition at 1 hrs, activity up to 2 hrs (30 mg/kg)

0.038 30/NA 39% inhibition at 1 hr, no activity up to follow hrs. (3mg/kg), 95% inhibition at 1 hr, activity up to 24 hrs (10 mg/kg), 70%inhibition at 2 hr, activity up to 24 hrs (30 mg/kg)

0.005 30/NA NSE (10 mg/kg)

0.012  0.010/3208 NSE (10 mg/kg)

0.003  0.010/2921 NSE (10 mg/kg)

0.007 30/NA NSE (10 mg/kg)

0.005 30/NA NSE (10 mpk)

0.004 0.0082/4239 N/A

n/a 0.0021/4203 N/A * NSE: not significant effect.

We claim:
 1. A compound of formula (I), or a pharmaceutically acceptablesalt thereof,

wherein: R is selected from the group consisting of aryl, arylalkyl,optionally substituted with one or more independent R¹⁰³ substituents;R₁ is selected from the group consisting of hydroxy, amino, alkyl,alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl,each optionally independently substituted with one or more independentR¹⁰³ substituents; R₂ is hydrogen; R₃ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl,—C(O)R¹⁰¹, —C(O)OR¹⁰¹, —C(O)NR¹⁰¹R¹⁰², —S(O)₂R¹⁰², —SR¹⁰¹ and—S(O)₂NR¹⁰¹R¹⁰², optionally substituted with one or more independentR¹⁰³ substituents; R₄ is selected from the group consisting of alkyl,alkenyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR¹⁰³, NR¹⁰¹R¹⁰²,—C(O)R¹⁰¹, —C(O)R¹⁰¹, —C(O)NR¹⁰¹R¹⁰², -alkylNR¹⁰¹R¹⁰², —S(O)₂R¹⁰²,—S(O)₂R¹⁰², —SR¹⁰¹, and —S(O)₂NR¹⁰¹R¹⁰², optionally substituted with oneor more independent R¹⁰³ substituents; R₅ is selected from the groupconsisting of alkyl, alkenyl, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, heteroarylalkyl, oxide (═O), —C(O)R¹⁰¹, —C(O)OR¹⁰¹,—C(O)NR¹⁰¹R¹⁰², —S(O)₂R¹⁰², —SR¹⁰¹ and —S(O)₂NR¹⁰¹R¹⁰²; R₆, R₇, R₈, R₉,R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are each independently selected from thegroup consisting of hydrogen, cyano, —NO₂, —OR¹⁰¹, hydroxy, amino,alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl,arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,heteroarylalkyl, —C(O)R¹⁰¹, —C(O)OR¹⁰¹, —C(O)NR¹⁰¹R¹⁰², —NR¹⁰¹R¹⁰²,—NR¹⁰¹S(O)₂R¹⁰², —NR¹⁰¹C(O)R¹⁰², —S(O)₂R¹⁰², —SR¹⁰¹ and —S(O)₂NR¹⁰¹R¹⁰²,each optionally independently substituted with one or more independentR¹⁰³ substituents; and R¹⁰¹, R¹⁰², and R¹⁰³ are each independentlyselected from the group consisting of hydrogen, cyano, —NO₂, —OR¹⁰⁴,hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy,alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl, heteroarylalkyl, —C(O)R¹⁰⁴, —C(O)OR¹⁰⁴, —C(O)NR¹⁰⁴R¹⁰⁵,—NR¹⁰⁴R¹⁰⁵, —NR¹⁰⁴S(O)₂R¹⁰⁵, —NR¹⁰⁴C(O)R¹⁰⁵, —S(O)₂R¹⁰⁴, —SR¹⁰⁴ and—S(O)₂NR¹⁰⁴R¹⁰⁵, each optionally independently substituted with one ormore independent R¹⁰³ substituents; or R¹⁰¹, R¹⁰², together with theatoms connecting the same, form a fused or non-fused mono, bicyclic ortricyclic heterocyclic or carbocyclic ring which is optionallyindependently substituted with one or more R¹⁰³ substituents; and R¹⁰⁴and R¹⁰⁵ are each independently selected from the group consisting ofhydrogen, cyano, —NO₂, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl,cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl.2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R is aryl.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R is phenyl ornaphthalene which is optionally independently substituted with from oneto six substituents independently selected from the group consisting ofhydrogen, chloro, fluoro, bromo, trifluoromethyl, cyano, methoxy,ethoxy, methyl and ethyl.
 4. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R₁ is selected fromthe group consisting of alkoxy, alkoxyalkyl, —OR¹⁰¹, hydroxy,hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl.5. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R₁ is selected from the group consisting of alkyl,cycloalkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl and heteroarylalkyl. 6.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R₁ is selected from the group consisting of methyl, —CH₂OH, and—CH₂—O—CH₂-phenyl.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R₃ is hydrogen, alkyl or cycloalkyl. 8.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R₄ is selected from the group consisting of alkyl, cycloalkyl,hydroxy, amino, alkoxy, alkylamino, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and aminoalkyl. 9.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R₄ is methyl, ethyl, benzyl, or benzyl substituted with from oneto five substituents independently selected from the group consisting ofmethyl, fluoro, chloro, trifluoromethyl, methoxy, cyano and hydroxy. 10.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R₅ is selected from the group consisting of alkyl, cycloalkyl,oxide (═O), aryl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,heteroarylalkyl, —C(O)R¹⁰¹, —C(O)OR¹⁰¹ and —C(O)NR¹⁰¹R¹⁰².
 11. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R₅ is methyl.
 12. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ andR₁₄ are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, —C(O)OR¹⁰¹, and -alkylOR¹⁰³.
 13. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R₈ and R₉ are each independently hydrogen, alkyl, cycloalkyl,—C(O)OR¹⁰¹, or -alkylOR¹⁰³.
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R₈ and R₉ are eachindependently hydrogen, methyl, ethyl, —C(═O)OEt, or —CH₂OH.
 15. Acompound selected from the group consisting of one of the followingcompounds, or a pharmaceutically acceptable salt thereof: GA1

1-methyl-3-((R)-1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA2

1-methyl-3-((S)-1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA3

1-methyl-3-(1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA4

3-(1-(4-methoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA5

1-benzyl-3-((R)-1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA6

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-methoxybenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA7

3-(1-(2,3-dichlorophenyl)ethyl)-1- (2-fluorobenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA8

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4- yl)urea, GA9

3-(1-(2,3-dichlorophenyl)ethyl)-1- methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA10

3-((R)-1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-(1,3-dimethylpiperidin-4-yl)-1-(3- methoxybenzyl)urea, GA11

1-benzyl-3-(1-(2,3- dichlorophenyl)propyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA12

3-((S)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA13

3-((R)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA14

3-(1-(2,3-dichlorophenyl)ethyl)-1- methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA15

1-benzyl-3-((S)-1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA16

1-benzyl-3-((R)-1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA17

1-benzyl-3-(1-(naphthalen-1- yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA18

3-(1-(2,3-dichlorophenyl)propyl)- 1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA19

3-(1-(2,3-difluorophenyl)ethyl)-1- methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA20

1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA21

1-benzyl-3-(1-(2,3- difluorophenyl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA22

1-benzyl-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA23

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA24

3-(1-(2,3-dichlorophenyl)ethyl)-1- methyl-1-(1,2,2,5,5-pentamethylpiperidin-4-yl)urea, GA25

methyl 2-(3-methyl-3-(1,3,3- trimethylpiperidin-4-yl)ureido)-2-(naphthalen-1-yl)acetate, GA26

3-(2-hydroxy-1-(naphthalen-1- yl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA27

1-(4-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA28

1-benzyl-1-(3,3-diethyl-1- methylpiperidin-4-yl)-3-((S)-1-(naphthalen-1-yl)ethyl)urea, GA29

1-benzyl-1-(3,3-diethyl-1- methylpiperidin-4-yl)-3-((R)-1-(naphthalen-1-yl)ethyl)urea, GA30

1-benzyl-1-(3,3-diethyl-1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA31

3-(2-(benzyloxy)-1-(naphthalen-1- yl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA32

ethyl 4-(1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)ureido)-1,3-dimethylpiperidine-3-carboxylate, GA33

3-((R)-1-(2,3- dichlorophenyl)ethyl)-1-(3- methoxybenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA34

3-(2-cyclopropyl-1-(2,3- dichlorophenyl)ethyl)-1-(3-methoxybenzyl)-1-(1,3,3- trimethylpiperidin-4-yl)urea, GA35

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-hydroxybenzyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA36

1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)-1-(3- (hydroxymethyl)-1,3-dimethylpiperidin-4-yl)urea, GA37

1-benzyl-3-(1-(2,3- dihydroxyphenyl)ethyl)-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA38

3-((R)-1-(2,3- dichlorophenyl)ethyl)-1-(3-(2-hydroxyethoxy)benzyl)-1-(1,3,3- trimethylpiperidin-4-yl)urea, GA39

3-(1-(2,3-difluoro-4- methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA40

3-(1-(2,3-difluoro-4- hydroxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA41

4-(1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)ureido)-1,3-dimethylpiperidine-3-carboxylic acid, GA42

ethyl 4-(3-(1-(2,3- dichlorophenyl)ethyl)-1- methylureido)-1,3-dimethylpiperidine-3-carboxylate, GA43

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-(hydroxymethyl)-1,3-dimethylpiperidin-4-yl)-1- methylurea, GA44

4-(3-(1-(2,3-dichlorophenyl)ethyl)- 1-methylureido)-1,3,3-trimethylpiperidine 1-oxide, GA45

3-(1-(benzo[d][1,3]dioxol-5- yl)ethyl)-1-benzyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA46

1-ethyl-1-(1-methylpiperidin-4-yl)- 3-(1-(naphthalen-1-yl)ethyl)urea,GA47

3-(1-(4-methoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA48

3-(2-hydroxy-1-(naphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA49

3-(2-hydroxy-1-(4- methoxynaphthalen-1-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA50

1-(1-methylpiperidin-4-yl)-3-(1- (naphthalen-1-yl)ethyl)-1-(pyridin-3-ylmethyl)urea, GA51

1-cyclopentyl-1-(1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA52

1-methyl-3-(1-(naphthalen-1- yl)ethyl)-1-(piperidin-4-yl)urea, GA53

1-(1-acetylpiperidin-4-yl)-1- methyl-3-(1-(naphthalen-1- yl)ethyl)urea,GA54

1-methyl-1-(1- (methylsulfonyl)piperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA55

1-methyl-3-(1-(naphthalen-1- yl)ethyl)-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)urea, GA56

1-cyclohexyl-1-(1-methylpiperidin- 4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA57

1-(cyclohexylmethyl)-1-(1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA58

1-isopropyl-1-(1-methylpiperidin- 4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA59

1-(2-methoxyethyl)-1-(1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA60

1-(1-ethylpiperidin-4-yl)-1-methyl- 3-(1-(naphthalen-1-yl)ethyl)urea,GA61

1-ethyl-4-(1-methyl-3-(1- (naphthalen-1- yl)ethyl)ureido)piperidine1-oxide, GA62

1-(cyclopropylmethyl)-1-(1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA63

3-(1-(2-methoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA64

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(quinolin-4-yl)ethyl)urea,GA65

tert-butyl 4-(1-methyl-3-(1- (naphthalen-1-yl)ethyl)ureido)piperidine-1- carboxylate, GA66

1-(1-formylpiperidin-4-yl)-1- methyl-3-(1-(naphthalen-1- yl)ethyl)urea,GA67

3-(2-methoxy-1-(naphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA68

3-(3-methoxy-1-(naphthalen-1- yl)propyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA69

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(naphthalen-1- yl)propyl)urea,GA70

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(quinolin-5-yl)ethyl)urea,GA71

1-methyl-1-(1-methylpiperidin-4- yl)-3-(2-(naphthalen-1-yl)propan-2-yl)urea, GA72

3-(1-(2-chloroquinolin-4-yl)ethyl)- 1-methyl-1-(1-methylpiperidin-4-yl)urea, GA73

(S)-1-(1-methylpiperidin-4-yl)-3- (1-(naphthalen-1-yl)ethyl)-1-(pyridin-3-ylmethyl)urea, GA74

(R)-1-(1-methylpiperidin-4-yl)-3- (1-(naphthalen-1-yl)ethyl)-1-(pyridin-3-ylmethyl)urea, GA75

1-isobutyl-1-(1-methylpiperidin-4- yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA76

1-(cyclobutylmethyl)-1-(1- methylpiperidin-4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA77

1-butyl-1-(1-methylpiperidin-4-yl)- 3-(1-(naphthalen-1-yl)ethyl)urea,GA78

3-(1-(2-methoxyquinolin-4- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA79

1-(1-methylpiperidin-4-yl)-3-(1- (naphthalen-1-yl)ethyl)-1-(pyridin-2-ylmethyl)urea, GA80

1-(1-methylpiperidin-4-yl)-3-(1- (naphthalen-1-yl)ethyl)-1-(pyridin-4-ylmethyl)urea, GA81

(S)-1-ethyl-3-(1-(2- methoxyquinolin-4-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA82

(R)-1-ethyl-1-(1-methylpiperidin- 4-yl)-3-(1-(naphthalen-1-yl)ethyl)urea, GA83

3-(2-hydroxy-1-(4- methoxynaphthalen-1-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA84

3-(2-hydroxy-1-(naphthalen-1- yl)ethyl)-1-(1-methylpiperidin-4-yl)-1-(pyridin-3-ylmethyl)urea, GA85

3-(2-methoxy-1-(4- methoxynaphthalen-1-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA86

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-hydroxybenzyl)-1-(1-methylpiperidin-4-yl)urea, GA87

1-benzyl-1-(1,3-dimethylpiperidin- 4-yl)-3-((R)-1-(naphthalen-1-yl)ethyl)urea, GA88

1-(1,3-dimethylpiperidin-4-yl)-1- methyl-3-((R)-1-(naphthalen-1-yl)ethyl)urea, GA89

3-(1-(4-methoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA90

(R)-3-(1-(4-methoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA91

(S)-3-(1-(4-methoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA92

3-(1-(4,8-dimethoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA93

3-(1-(4- (methoxymethoxy)naphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA94

3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA95

(R)-3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA96

(S)-3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA97

3-(1-(2,3-dichlorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4-yl)urea, GA98

1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA99

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea, GA100

1-(2-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA101

3-(1-(3,5-difluorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4-yl)urea, GA102

3-(1-(2-chlorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4- yl)urea,GA103

3-(1-(3-fluorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4- yl)urea,GA104

3-(1-(4-chlorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4- yl)urea,GA105

3-(1-(2,4-difluorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4-yl)urea, GA106

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(o-tolyl)ethyl)urea, GA107

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(4-(methylsulfonyl)phenyl)ethyl)urea, GA108

1-(cyclohexylmethyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA109

1-(cyclopropylmethyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA110

3-(1-(2,3-dichlorophenyl)ethyl)-1- ethyl-1-(1-methylpiperidin-4-yl)urea, GA111

3-(1-(2,3-dichlorophenyl)ethyl)-1- (1-methylpiperidin-4-yl)-1-(pyridin-3-ylmethyl)urea, GA112

3-(1-(3-chlorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4- yl)urea,GA113

1-benzyl-3-(1-(3- chlorophenyl)ethyl)-1-(1- methylpiperidin-4-yl)urea,GA114

1-(3-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA115

3-(1-(2,3-dichlorophenyl)ethyl)-1- (2-methoxybenzyl)-1-(1-methylpiperidin-4-yl)urea, GA116

3-(1-(2,3-dichlorophenyl)ethyl)-1- (3-methoxybenzyl)-1-(1-methylpiperidin-4-yl)urea, GA117

3-(1-(2,3-dichlorophenyl)ethyl)-1- (4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea, GA118

3-(1-(2,3-dichlorophenyl)ethyl)-1- (2-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea, GA119

1-(4-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA120

3-(1-(3,4-dichlorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4-yl)urea, GA121

3-(1-(2,3-dichlorophenyl)ethyl)-1- (4-methoxybenzyl)-1-(1-methylpiperidin-4-yl)urea, GA122

3-(1-(2,3-dichlorophenyl)propyl)- 1-ethyl-1-(1-methylpiperidin-4-yl)urea, GA123

1-(cyclohexylmethyl)-3-(1-(2,3- dichlorophenyl)propyl)-1-(1-methylpiperidin-4-yl)urea, GA124

3-(1-(2,3-difluorophenyl)ethyl)-1- methyl-1-(1-methylpiperidin-4-yl)urea, GA125

1-benzyl-3-(1-(2,3- difluorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA126

1-(cyclohexylmethyl)-3-(1-(2,3- difluorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA127

(R)-3-(1-(2,3- dichlorophenyl)ethyl)-1-ethyl-1-(1-methylpiperidin-4-yl)urea, GA128

1-benzyl-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1,3-dimethylpiperidin-4-yl)urea, GA129

3-(1-(2,3-dichlorophenyl)ethyl)-1- (1,3-dimethylpiperidin-4-yl)-1-methylurea, GA130

(S)-3-(1-(2,3- dichlorophenyl)ethyl)-1-ethyl-1-(1-methylpiperidin-4-yl)urea, GA131

(R)-3-(1-(2,3- dichlorophenyl)ethyl)-1-ethyl-1-(1-methylpiperidin-4-yl)urea, GA132

3-(1-(2,3-dichlorophenyl)ethyl)-1- ethyl-1-(1-methylpiperidin-4-yl)urea, GA133

3-((R)-1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-(1,3-dimethylpiperidin-4-yl)-1-(3- methoxybenzyl)urea, GA134

3-((S)-1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-(1,3-dimethylpiperidin-4-yl)-1-(3- methoxybenzyl)urea, GA135

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-(1,3-dimethylpiperidin-4-yl)-1-(3- methoxybenzyl)urea, GA136

3-(1-(2,3-difluorophenyl)ethyl)-1- (1,3-dimethylpiperidin-4-yl)-1-(3-methoxybenzyl)urea, GA137

3-(1-(2,3-dichlorophenyl)ethyl)-1- (4-(hydroxymethyl)benzyl)-1-(1-methylpiperidin-4-yl)urea, GA138

methyl 4-((3-(1-(2,3- dichlorophenyl)ethyl)-1-(1- methylpiperidin-4-yl)ureido)methyl)benzoate, GA139

3-(2-cyclopropyl-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA140

3-(1-(2,3-dichlorophenyl)-2- hydroxyethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA141

(R)-1-(2-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA142

(S)-1-(2-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA143

1-(2-chlorobenzyl)-3-(1-(2,3- dichlorophenyl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA144

3-(1-(2,3-dimethoxyphenyl)ethyl)- 1-methyl-1-(1-methylpiperidin-4-yl)urea, GA145

3-(1-(2,3-difluoro-4- methoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA146

3-(1-(2,3-dichlorophenyl)-2- methoxyethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA147

N-(2,3-dichloro-4-(1-(3-methyl-3- (1-methylpiperidin-4-yl)ureido)ethyl)phenyl)acetamide, GA148

3-(1-(4-amino-2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA149

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA150

1-ethyl-1-(1-methylpiperidin-4-yl)- 3-(1-(naphthalen-1-yl)-3-(3-(pyridin-3- yloxy)phenyl)propyl)urea, GA151

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(naphthalen-1-yl)-3-(pyridin-3-yl)propyl)urea, GA152

1-methyl-1-(1-methylpiperidin-4- yl)-3-(3-morpholino-1-(naphthalen-1-yl)propyl)urea, GA153

1-ethyl-3-(3-(3-methoxyphenyl)-1- (naphthalen-1-yl)propyl)-1-(1-methylpiperidin-4-yl)urea, GA154

3-(3-(3-(benzyloxy)phenyl)-1- (naphthalen-1-yl)propyl)-1-ethyl-1-(1-methylpiperidin-4-yl)urea, GA155

1-ethyl-1-(1-methylpiperidin-4-yl)- 3-(1-(naphthalen-1-yl)-3-(pyridin-3-yl)propyl)urea, GA156

3-(3-(3-(benzyloxy)phenyl)-1- (naphthalen-1-yl)propyl)-1-(1-methylpiperidin-4-yl)-1-(pyridin-3- ylmethyl)urea, GA157

3-(3-(3-(benzyloxy)phenyl)-1-(2,3- dichlorophenyl)propyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA158

3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA159

3-(2-(benzylamino)-1-(2,3- dichlorophenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA160

3-(1-(2,3-dichlorophenyl)-2((3- (hydroxymethyl)benzyl)oxy)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA161

3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-(2- chlorobenzyl)-1-(1-methylpiperidin-4-yl)urea, GA162

3-(2-(benzyloxy)-1-(2,3- dichlorophenyl)ethyl)-1-(4-(hydroxymethyl)benzyl)-1-(1- methylpiperidin-4-yl)urea, GA163

3-(1-(2,3-dichlorophenyl)-2-((4- methoxybenzyl)oxy)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA164

3-(1-(2,3-dichlorophenyl)-2- (pyridin-4-ylmethoxy)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA165

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methoxy-1-(1-methylpiperidin-4-yl)urea, GA166

(S)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methoxy-1-(1-methylpiperidin-4-yl)urea, GA167

(R)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methoxy-1-(1-methylpiperidin-4-yl)urea, GA168

1-hydroxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA169

(R)-1-hydroxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA170

(S)-1-hydroxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA171

3-(1-(2,3-dichlorophenyl)ethyl)-1- methoxy-1-(1-methylpiperidin-4-yl)urea, GA172

(R)-3-(1-(2,3- dichlorophenyl)ethyl)-1-methoxy-1-(1-methylpiperidin-4-yl)urea, GA173

(S)-3-(1-(2,3- dichlorophenyl)ethyl)-1-methoxy-1-(1-methylpiperidin-4-yl)urea, GA174

1-methoxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA175

(R)-1-methoxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA176

(S)-1-methoxy-3-(1-(4- methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea, GA177

3-(1-(2,3-dichlorophenyl)ethyl)-1- hydroxy-1-(1-methylpiperidin-4-yl)urea, GA178

(R)-3-(1-(2,3- dichlorophenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, GA179

(S)-3-(1-(2,3- dichlorophenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, GA180

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, GA181

(R)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, GA182

(S)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea, GA183

3-(1-(2,3-dichloro-4- (dimethylamino)phenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA184

3-(1-(4-((4- methoxybenzyl)oxy)naphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA185

3-(1-(4-hydroxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA186

3-(1-(4,5-dimethoxynaphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA187

3-(1-(2,3-dichlorophenyl)-2- (pyridin-3-ylmethoxy)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA188

3-(1-(4-chlorobenzo[d][1,3]dioxol- 5-yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA189

3-(1-(2-chloro-3,4- dimethoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA190

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(2,3,4-trichlorophenyl)ethyl)urea, GA191

1-methyl-1-(1-methylpiperidin-4- yl)-3-(1-(4-(pyridin-4-ylmethoxy)naphthalen-1- yl)ethyl)urea, GA192

3-(1-(6-chloro-[1,1′-biphenyl]-2- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA193

3-(1-(3-chloro-2-(pyridin-4- yl)phenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA194

3-(1-(2,3-dichloro-4- methylphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA195

3-(1-(3-chloro-2- methylphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA196

3-(1-(2,3-dichlorophenyl)-2-((4- (hydroxymethyl)benzyl)oxy)ethyl)-1-methyl-1-(1-methylpiperidin-4- yl)urea, GA197

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA198

(R)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA199

(S)-3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea, GA200

3-(1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA201

3-((R)-1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea, GA202

3-((S)-1-(2,3-dichloro-4- methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin- 4-yl)urea, and GA203

3-(1-(4-(2- (benzyloxy)ethoxy)naphthalen-1- yl)ethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea.


16. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1, and one or morepharmaceutically acceptable excipients. 17.3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea(GA23), or a pharmaceutically acceptable salt thereof. 18.1-hydroxy-3-(1-(4-methoxynaphthalen-1-yl)ethyl)-1-(1-methylpiperidin-4-yl)urea(GA168), or a pharmaceutically acceptable salt thereof. 19.3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-hydroxy-1-(1-methylpiperidin-4-yl)urea(GA180), or a pharmaceutically acceptable salt thereof.